TMA16 (Translation Machinery-Associated Protein 16): A Comprehensive Review

Introduction

TMA16 (Translation machinery-associated protein 16), also known by its former designation C4orf43, is a human nuclear protein that functions as an assembly factor in the biogenesis of the large (60S) ribosomal subunit. Encoded by the TMA16 gene located on chromosome 4, this 203-amino acid protein (UniProt: Q96EY4) has been structurally characterized as binding to pre-60S ribosomal particles during their late nuclear maturation stages, specifically occupying a strategic position between the rotated 5S ribonucleoprotein (5S RNP) complex and the P0 stalk [liang-2020-pre60S-summary]. Despite its recent structural characterization, TMA16 remains relatively understudied compared to other ribosome biogenesis factors, with the majority of functional insights derived from a single seminal cryo-electron microscopy study published in 2020.

The protein belongs to the conserved TMA16 family and contains the Tma16 domain (Pfam: PF11176, InterPro: IPR021346), which is found across eukaryotes from yeast to humans. Gene Ontology annotations based on direct experimental evidence indicate that TMA16 functions in preribosome binding and ribosomal large subunit biogenesis, with localization to the nucleus, nucleoplasm, and nucleolus [GO-annotations]. The primary function of TMA16 appears to be as a transient stabilizing factor that associates with pre-60S particles following the critical 5S RNP rotation event and dissociates before the particles undergo nuclear export and subsequent cytoplasmic maturation.

Molecular Function and Structural Basis

The molecular function of TMA16 was elucidated through cryo-electron microscopy structural analysis of human pre-60S ribosomal particles purified via the nuclear export factor NMD3 [liang-2020-pre60S-summary]. According to PubMed, Liang and colleagues (DOI) determined four structures representing assembly stages immediately before and after nuclear export, revealing TMA16 as a previously uncharacterized factor positioned in the space between the rotated 5S RNP and the P0 stalk.

The structural analysis enabled construction of an atomic model for residues 17-166 of the full-length 203-residue protein [liang-2020-pre60S-summary]. The N-terminus of TMA16 contains a remarkably long alpha-helix spanning residues 19-60, extending approximately 60 angstroms toward the peptidyl transferase center (PTC). The N-terminal end of this helix docks onto the tip of helix 39 (H39) of the 28S ribosomal RNA, with two highly conserved residues, H18 and R22, forming direct interactions with nucleotides A1867 and G1864 of H39 respectively. This N-terminal helix also engages in extensive interactions with the 5S RNA, primarily through its basic residues.

The main body of TMA16 adopts a position sandwiched between rRNA helices H42 and H25ES7. One side of TMA16, comprising the loop between helices H1 and H2 and the C-terminal region, interacts with H25ES7, while the opposite side containing the loop between H2 and H3 specifically contacts H42 [liang-2020-pre60S-summary]. This strategic positioning suggests that TMA16 may function as a sensor for the rotational state of the 5S RNP, stabilizing the pre-60S particle in a conformation appropriate for nuclear export.

The interaction between TMA16 and H39 is further stabilized by the assembly factor GTPBP4 (known as Nog2 in yeast). Specifically, residue Y124 of the GTPBP4 N-terminal domain enhances the stacking interaction between H18 of TMA16 and A1867 of H39 [liang-2020-pre60S-summary]. This tripartite interaction network indicates that TMA16 function is integrated with the broader assembly factor machinery controlling pre-60S maturation.

TMA16 has also been annotated with the molecular function "protein-macromolecule adaptor activity" (GO:0030674) based on direct assay evidence from the Liang et al. study [GO-annotations]. This annotation reflects the structural role of TMA16 in bridging between the 5S RNP complex and the ribosomal RNA elements of the maturing 60S subunit. High-throughput interactome mapping studies have identified physical interactions between TMA16 and proteins including AP2M1, CASTOR1, HTT (huntingtin), KLHL2, KRTAP10-7, and TSPYL2, although the functional significance of these interactions remains to be determined [rolland-2014-interactome-abstract].

Subcellular Localization

TMA16 localizes to the nucleus, consistent with its function in the nuclear stages of ribosome biogenesis. According to annotations from the Human Protein Atlas (HPA) based on direct assay evidence, TMA16 is found in both the nucleoplasm and nucleolus [GO-annotations]. This dual localization is consistent with the known pathway of 60S ribosome biogenesis, which initiates in the nucleolus and progresses through the nucleoplasm before particles are exported to the cytoplasm.

The nucleolar localization positions TMA16 appropriately for its role in pre-60S maturation, as this is where the majority of ribosomal RNA transcription and early processing occurs. The nucleoplasmic localization reflects the later maturation stages where TMA16 is structurally observed to associate with pre-60S particles that have completed 5S RNP rotation but have not yet undergone nuclear export [liang-2020-pre60S-summary].

Additional localization data from high-throughput studies supports nuclear localization of TMA16, with the protein detected in the human sperm nucleus proteome (DOI, PMID: 21630459).

Role in 60S Ribosome Biogenesis

Eukaryotic ribosome biogenesis is an extraordinarily complex process involving over 200 assembly factors and approximately 76 small nucleolar RNAs working in concert to fold, modify, and process ribosomal RNA while coordinating binding of ribosomal proteins [konikkat-2017-60S-review-abstract]. The large 60S ribosomal subunit assembly pathway proceeds through the nucleolus and nucleoplasm before particles undergo Crm1-dependent nuclear export and final cytoplasmic maturation.

A landmark discovery in understanding 60S biogenesis was the demonstration that the 5S RNP complex, consisting of 5S rRNA bound to ribosomal proteins L5 (uL18) and L11 (uL5), undergoes a dramatic ~180-degree rotation during maturation [leidig-2014-5SRNP-rotation-abstract]. According to PubMed, Leidig and colleagues (DOI) showed using cryo-EM that the 5S RNP is initially positioned in a pre-rotation conformation that is nearly opposite its final mature position on the 60S subunit. This rotation is coordinated with remodeling of neighboring 25S rRNA helices and is stabilized by assembly factors including Rsa4 and Nog1.

TMA16 enters the pre-60S assembly pathway after the 5S RNP rotation has occurred. The structural analysis by Liang et al. shows that TMA16 binds in the space that opens up between the rotated 5S RNP and the P0 stalk [liang-2020-pre60S-summary]. Critically, TMA16 is present in the earlier maturation states (pre-A and A) but absent from the later states (B and C), indicating that its association with pre-60S particles is transient.

The timing of TMA16 action is constrained by incompatibilities with both earlier and later assembly factors. TMA16 binding is incompatible with factors that act earlier than NMD3, including Nug1 and Cgr1, which are present in nucleoplasmic Nog2-particles [liang-2020-pre60S-summary]. It also has a steric clash with the ribosomal protein uL16, which is incorporated at later stages. These observations define a relatively narrow time window for TMA16 function: after 5S RNP rotation and before the departure of GTPBP4.

The observation that TMA16 is absent from equivalent positions in yeast pre-60S structures at similar maturation stages suggests that TMA16 may be a transient binding factor whose association timing is strictly controlled [liang-2020-pre60S-summary]. This transient nature, combined with its strategic position sensing the 5S RNP rotation state, has led to the suggestion that TMA16 may function as a structural checkpoint or nuclear export adapter. In yeast, Tma16 has been found in pre-60S particles purified through Arx1 or Lsg1, and accumulates on pre-60S Lsg1-particles when Nog1 release is impaired, supporting a role in the export-proximate stages of assembly.

Conservation and Evolutionary Context

TMA16 is conserved across eukaryotes, with identifiable homologs from yeast (Saccharomyces cerevisiae) to humans. The Tma16 domain (PF11176) that defines this protein family is found in all major eukaryotic lineages, indicating an ancient origin and fundamental importance in ribosome biogenesis.

Despite this conservation at the sequence level, there appear to be species-specific differences in the behavior of TMA16 family proteins. As noted above, human TMA16 was clearly resolved in cryo-EM structures of pre-60S particles, whereas the equivalent position appears empty in yeast structures at comparable maturation stages [liang-2020-pre60S-summary]. This may reflect differences in the kinetics of TMA16 association and dissociation between species, or could indicate that the protein is more stably associated with pre-60S particles in humans than in yeast.

A comprehensive proteomics study of yeast 60S ribosome biogenesis factors provided important insights into yeast Tma16 interactions. Sailer and colleagues (DOI) used cross-linking mass spectrometry to identify interactions between the N-terminal region of Tma16 and Rei1 (a cytoplasmic assembly factor), as well as between the C-terminal region of Tma16 and ribosomal protein uL18 [sailer-2022-60S-landscape-abstract]. Since uL18 and Rei1 are located distantly from each other on the pre-60S surface, this suggests that yeast Tma16 adopts an extended conformation bridging these sites. The abundance pattern of Tma16 in various pre-60S particle preparations was most similar to the Arx1/Alb1 complex, consistent with its role at cytoplasmic maturation stages. These data support classification of yeast Tma16 as a cytoplasmic ribosome biogenesis factor, somewhat later than the nuclear localization observed for human TMA16.

Phenotypic analysis of yeast TMA16 (YOR252W) deletion mutants from the Saccharomyces Genome Database reveals that TMA16 is not essential for viability [SGD-TMA16]. The null mutant phenotypes include altered competitive fitness, haploinsufficiency, decreased heat sensitivity, and abnormal vacuolar morphology. The SGD describes yeast TMA16 as a "protein of unknown function that associates with ribosomes." Interestingly, the yeast gene has 121 documented physical interactions across 104 unique genes, including numerous ribosomal proteins and biogenesis factors identified through affinity capture-mass spectrometry approaches. The transcription of yeast TMA16 is regulated by stress-responsive transcription factors Yap6p (heat response) and Sfp1p (stress response), consistent with coordination of its expression with ribosome biogenesis rates.

A recent comprehensive structural analysis comparing human and yeast ribosome biogenesis confirmed the high degree of conservation in the overall pathway. According to PubMed, Fiorentino and colleagues (DOI) demonstrated that the interaction networks and conformational changes during 60S assembly are essentially identical between yeast and humans, supporting the evolutionary preservation of ribosomal assembly mechanisms.

Regulation of TMA16 Expression

While relatively little is known about the transcriptional or post-transcriptional regulation of human TMA16, studies in yeast have revealed that TMA16 mRNA levels are regulated by P-body proteins during cellular stress. According to PubMed, Loll-Krippleber and Brown (DOI) identified yeast TMA16 as one of six mRNAs (including HHT1, ACF4, ARL3, RRS1, and YOX1) whose abundance is controlled by the P-body protein Lsm1 during DNA replication stress induced by hydroxyurea treatment [loll-krippleber-2017-pbody-abstract].

P-bodies are cytoplasmic granules that form in response to various stresses and serve as sites for mRNA storage and degradation. The finding that Lsm1 controls TMA16 mRNA abundance to prevent its "toxic accumulation" during replication stress suggests that TMA16 overexpression may be detrimental under stress conditions. This could relate to the importance of precisely controlling ribosome biogenesis rates during cellular stress responses.

At the protein level, TMA16 has been found to undergo post-translational modifications including ADP-ribosylation at serine-9 and O-linked glycosylation. Three genetic variants have been documented in human populations: R12Q, Q65P, and I176T, though no disease associations have been established for these variants.

Implications for Disease

TMA16 has not been directly implicated as a causative gene in any disease to date. However, given its role in ribosome biogenesis, it may be relevant to the class of disorders known as ribosomopathies, which result from defects in ribosome production or function. Ribosomopathies include Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and others, typically caused by mutations in ribosomal proteins or core biogenesis factors.

TMA16 was identified as a differentially methylated gene in a study of Parkinson's disease biomarkers. According to PubMed, Zhu and colleagues (DOI) found TMA16 among a small set of genes with altered methylation patterns in both cerebrospinal fluid and blood cell-free DNA of Parkinson's disease patients. The significance of this finding for disease pathophysiology remains to be determined.

Additionally, a genome-wide association study in Korean women identified TMA16 among genes associated with body mass index and basal metabolic rate (DOI, PMID: 26865924), though these associations require replication and functional validation.

Open Questions

Despite significant advances in understanding TMA16 structure and localization, several important questions remain:

1. Precise molecular function: While TMA16 clearly associates with pre-60S particles at specific maturation stages, its exact biochemical function remains unclear. Does it actively promote structural transitions, or does it serve primarily as a passive stabilizer? The suggestion that it could function as a nuclear export adapter requires experimental validation.

2. Mechanism of association and release: What signals trigger TMA16 binding to pre-60S particles after 5S RNP rotation, and what causes its release? The dependence on GTPBP4 for stabilizing the TMA16-H39 interface suggests that GTPBP4 departure may trigger TMA16 release, but this has not been directly tested.

3. Species-specific differences: Why is TMA16 visible in human pre-60S structures but not in yeast structures at comparable stages? This could reflect genuine differences in TMA16 function between species or could be a technical artifact of particle isolation conditions.

4. Functional significance of protein interactions: The high-throughput identification of TMA16 interacting partners (AP2M1, CASTOR1, HTT, etc.) raises questions about potential functions beyond ribosome biogenesis. Are these interactions physiologically relevant?

5. Consequences of TMA16 deficiency: In yeast, TMA16 deletion mutants are viable, with phenotypes including altered competitive fitness, haploinsufficiency, decreased heat sensitivity, and abnormal vacuolar morphology [SGD-TMA16]. This suggests Tma16 is not essential for ribosome biogenesis in yeast. No detailed characterization of TMA16 knockout or knockdown phenotypes in mammalian cells has been published. Such studies would clarify whether human TMA16 has a more essential or modulatory role.

6. Post-translational modifications: The functional significance of ADP-ribosylation at serine-9 and O-linked glycosylation of TMA16 is unknown. Could these modifications regulate TMA16 localization or activity?

7. Disease relevance: Does TMA16 contribute to ribosomopathies or other diseases? The methylation changes observed in Parkinson's disease warrant further investigation.

References

1. liang-2020-pre60S: Liang X, Zuo MQ, Zhang Y, Li N, Ma C, Dong MQ, Gao N. Structural snapshots of human pre-60S ribosomal particles before and after nuclear export. Nature Communications. 2020 Jul 15;11(1):3542. PMID: 32669547. PMCID: PMC7363849. DOI: 10.1038/s41467-020-17237-x

2. loll-krippleber-2017-pbody: Loll-Krippleber R, Brown GW. P-body proteins regulate transcriptional rewiring to promote DNA replication stress resistance. Nature Communications. 2017 Sep 15;8(1):558. PMID: 28916784. PMCID: PMC5601920. DOI: 10.1038/s41467-017-00632-2

3. konikkat-2017-60S-review: Konikkat S, Woolford JL Jr. Principles of 60S ribosomal subunit assembly emerging from recent studies in yeast. Biochemical Journal. 2017 Jan 15;474(2):195-214. PMID: 28062837. PMCID: PMC5555582. DOI: 10.1042/BCJ20160516

4. leidig-2014-5SRNP-rotation: Leidig C, Thoms M, Holdermann I, Bradatsch B, Berninghausen O, Bange G, Sinning I, Hurt E, Beckmann R. 60S ribosome biogenesis requires rotation of the 5S ribonucleoprotein particle. Nature Communications. 2014 Mar 24;5:3491. PMID: 24662372. DOI: 10.1038/ncomms4491

5. ma-2017-cytoplasmic-pre60S: Ma C, Wu S, Li N, Chen Y, Yan K, Li Z, Zheng L, Lei J, Woolford JL, Gao N. Structural snapshot of cytoplasmic pre-60S ribosomal particles bound by Nmd3, Lsg1, Tif6 and Reh1. Nature Structural & Molecular Biology. 2017 Mar;24(3):214-220. PMID: 28112732. PMCID: PMC5555584. DOI: 10.1038/nsmb.3364

6. vanden-broeck-2023-human-pre60S: Vanden Broeck A, Klinge S. Principles of human pre-60S biogenesis. Science. 2023 Jul 7;381(6653):eadh3892. PMID: 37410842. DOI: 10.1126/science.adh3892

7. rolland-2014-interactome: Rolland T, Taşan M, Charloteaux B, et al. A proteome-scale map of the human interactome network. Cell. 2014 Nov 20;159(5):1212-1226. PMID: 25416956. PMCID: PMC4266588. DOI: 10.1016/j.cell.2014.10.050

8. luck-2020-HuRI-interactome: Luck K, Kim DK, Lambourne L, et al. A reference map of the human binary protein interactome. Nature. 2020 Apr;580(7803):402-408. PMID: 32296183. PMCID: PMC7169983. DOI: 10.1038/s41586-020-2188-x

9. thoms-2018-5SRNP-cgr1: Thoms M, Mitterer V, Kater L, Falquet L, Beckmann R, Kressler D, Hurt E. Suppressor mutations in Rpf2-Rrs1 or Rpl5 bypass the Cgr1 function for pre-ribosomal 5S RNP-rotation. Nature Communications. 2018 Oct 5;9(1):4094. PMID: 30291245. PMCID: PMC6173701. DOI: 10.1038/s41467-018-06660-w

10. thoms-2023-rixosome: Thoms M, Lau B, Cheng J, et al. Structural insights into coordinating 5S RNP rotation with ITS2 pre-RNA processing during ribosome formation. EMBO Reports. 2023 Dec;24(12):e57984. PMID: 37921038. PMCID: PMC10702828. DOI: 10.15252/embr.202357984

11. fiorentino-2025-MDN1-NLE1: Fiorentino F, Thoms M, Wild K, Denk T, Cheng J, Zeman J, Sinning I, Hurt E, Beckmann R. Highly conserved ribosome biogenesis pathways between human and yeast revealed by the MDN1-NLE1 interaction and NLE1 containing pre-60S subunits. Nucleic Acids Research. 2025 Apr 10;53(7). PMID: 40207627. PMCID: PMC11983104. DOI: 10.1093/nar/gkaf255

12. nerurkar-2015-ribosome-export-review: Nerurkar P, Altvater M, Gerhardy S, Schütz S, Fischer U, Weirich C, Panse VG. Eukaryotic Ribosome Assembly and Nuclear Export. International Review of Cell and Molecular Biology. 2015;319:107-40. PMID: 26404467. DOI: 10.1016/bs.ircmb.2015.07.002

13. UniProt Q96EY4: UniProt Consortium. UniProt entry Q96EY4 (TMA16_HUMAN). https://www.uniprot.org/uniprotkb/Q96EY4

14. de-mateo-2011-sperm-nucleus: de Mateo S, Castillo J, Estanyol JM, Ballescà JL, Oliva R. Proteomic characterization of the human sperm nucleus. Proteomics. 2011 Jun;11(13):2714-26. PMID: 21630459. DOI: 10.1002/pmic.201000799

15. sailer-2022-60S-landscape: Sailer C, Jansen J, Sekulski K, Cruz VE, Erzberger JP, Stengel F. A comprehensive landscape of 60S ribosome biogenesis factors. Cell Reports. 2022 Feb 8;38(6):110353. PMID: 35139378. PMCID: PMC8884084. DOI: 10.1016/j.celrep.2022.110353

16. SGD-TMA16: Saccharomyces Genome Database. TMA16/YOR252W Gene Entry. https://www.yeastgenome.org/locus/S000005778

Citations

1. SGD-TMA16-entry.md
2. konikkat-2017-60S-review-abstract.md
3. leidig-2014-5SRNP-rotation-abstract.md
4. liang-2020-pre60S-abstract.md
5. liang-2020-pre60S-fulltext.txt
6. liang-2020-pre60S-summary.md
7. loll-krippleber-2017-pbody-abstract.md
8. loll-krippleber-2017-pbody-fulltext.txt
9. luck-2020-HuRI-abstract.md
10. ma-2017-cytoplasmic-pre60S-abstract.md
11. rolland-2014-interactome-abstract.md
12. sailer-2022-60S-landscape-abstract.md
13. thoms-2018-cgr1-abstract.md
14. vanden-broeck-2023-human-pre60S-abstract.md

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

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We verified identity and nomenclature, gathered recent and foundational evidence on localization, stage, and molecular role, extracted application/disease-relevant mentions, synthesized a mechanistic narrative, and summarized key facts in a reference table for quick review.

Table: Concise, evidence-backed summary of human TMA16 (UniProt Q96EY4) covering identity, localization, ribosome-stage association, interactions, structural notes, functional role, links to translation/RQC, disease proteomics, and cross-species (yeast) data with source URLs and publication dates.

Comprehensive research report: Human TMA16 (UniProt Q96EY4; gene symbol TMA16; alias C4orf43)

1) Key concepts and definitions (current understanding)
- Identity and family: TMA16 encodes translation machinery-associated protein 16, a conserved member of the TMA16 family (PF11176). In human proteomic resources, it is indexed as Q96EY4 (alias C4orf43). Recent large-scale proteomics mention TMA16 explicitly by UniProt ID (Q96EY4) in cancer unfoldome analyses, confirming protein identity in human datasets (though not placed in their interaction network) (https://doi.org/10.3390/ijms25031552; published 26 Jan 2024) (paromov2024theproteomicanalysis pages 1-2).
- Conceptual role: Across eukaryotes, Tma16 proteins are ribosome-associated factors (RAFs) implicated in large subunit (pre-60S) maturation/export steps rather than enzymatic catalysis. Foundational yeast work systematically identified TMA proteins as ribosome-associated and affecting translation phenotypes, establishing a conserved functional class to which Tma16 belongs (https://doi.org/10.1101/gad.1422006; 22 May 2006) (fleischer2006systematicidentificationand pages 7-8).

2) Recent developments and latest research (2023–2024 priority)
- Association with pre-60S export/maturation modules in live cells: High-speed single-molecule microscopy of human pre-ribosomal subunits quantified nuclear export and collated accessory proteins, listing eIF6, TMA16, LLPH, and NMD3 among factors associated with pre-60S export/maturation, supporting a role for human TMA16 in late pre-60S biology (https://doi.org/10.1016/j.isci.2023.107445; 18 Aug 2023) (junod2023dynamicsofnuclear pages 6-10).
- Structural context from cryo-EM: In structural studies visualizing Drg1-mediated extraction of Rlp24 from pre-60S particles, authors note “weak density for Tma16 at the position reported in mammalian pre-60S,” and broadly that structural information for some pre-60S assembly factors including Tma16 remains limited. This places Tma16 at a defined site on mammalian pre-60S but underscores incomplete structural resolution (https://doi.org/10.1038/s41594-022-00832-5; 12 Sep 2022) (prattes2022visualizingmaturationfactor pages 7-8).
- Network placement with translation initiation machinery: An analysis of cancer-linked EIF4G2 (a non-canonical translation initiation factor) reports newly identified interacting proteins that include ribosome assembly factors such as TMA16, situating TMA16 within broader translation-initiation/assembly interaction landscapes in human cells (https://doi.org/10.26508/lsa.202302338; 2 Dec 2024) (meril2024lossoffunctioncancerlinkedmutations pages 7-8).
- Cancer proteomics context: A 2024 proteomics study of breast cancer “unfoldome” (IDP/IDPR-enriched proteome) identifies TMA16 by UniProt ID but notes it was not included in the resulting interactivity network, indicating detection without strong network integration in that dataset (https://doi.org/10.3390/ijms25031552; 26 Jan 2024) (paromov2024theproteomicanalysis pages 1-2).

3) Current applications and real-world implementations
- Ribosome biogenesis/export biology: Live-cell imaging quantifies pre-60S export times (13 ± 1 ms) and pre-40S (9 ± 1 ms) through nuclear pore complexes and lists TMA16 among pre-60S accessory/export factors. While these statistics describe subunit dynamics, they contextualize TMA16’s likely stage and compartment of action during pre-60S nuclear export and early cytoplasmic maturation (https://doi.org/10.1016/j.isci.2023.107445; 18 Aug 2023) (junod2023dynamicsofnuclear pages 6-10).
- Translational networks and disease research: EIF4G2-focused human studies that list TMA16 among assembly factors map potential interfaces between translation initiation and ribosome assembly, relevant to oncology-focused translation control research (https://doi.org/10.26508/lsa.202302338; 2 Dec 2024) (meril2024lossoffunctioncancerlinkedmutations pages 7-8).

4) Expert opinions and analysis from authoritative sources
- Ribosome maturation context: Pre-60S cytoplasmic maturation, governed by the AAA-ATPase Drg1 and the GTPase Nog1/NOG2 pathways, has been dissected in detail. Although specific direct biochemistry for human TMA16 remains sparse, authoritative work notes Tma16 as a nuclear-localized assembly factor in pre-60S maturation lists and that structural information for Tma16 on pre-60S is lacking, consistent with an accessory/adapter function rather than a catalytic role (eLife perspective on Nog1 and maturation coordination, 7 Jan 2020: https://doi.org/10.7554/eLife.52474) (purnima2020thegtpasenog1 pages 1-3); structural analysis of Drg1 action and mention of Tma16 placement/density, 12 Sep 2022: https://doi.org/10.1038/s41594-022-00832-5 (prattes2022visualizingmaturationfactor pages 7-8).
- Yeast functional screens: Systematic identification of ribosome-associated proteins (including TMA family members) and translation phenotyping in yeast provide a comparative framework supporting conserved ribosome-association for Tma16 homologs (https://doi.org/10.1101/gad.1422006; 22 May 2006) (fleischer2006systematicidentificationand pages 7-8).

5) Relevant statistics and data from recent studies
- Pre-ribosomal subunit export kinetics: In live human cells, successful nuclear export time for pre-60S is 13 ± 1 ms and for pre-40S is 9 ± 1 ms (single-molecule measurements). These data frame the time window in which pre-60S export adapters/accessories (including TMA16, eIF6, NMD3, LLPH) act (https://doi.org/10.1016/j.isci.2023.107445; 18 Aug 2023) (junod2023dynamicsofnuclear pages 6-10).
- Cancer proteomics coverage: The 2024 breast cancer unfoldome analysis reports 2,271 protein groups in unfoldome fractions, with 148 intrinsically disordered proteins (IDPs) differentially expressed. TMA16 (Q96EY4) is detected but excluded from the final interaction network, indicating presence yet uncertain network connectivity in that dataset (https://doi.org/10.3390/ijms25031552; 26 Jan 2024) (paromov2024theproteomicanalysis pages 1-2).

Functional annotation and mechanistic model
- Subcellular localization: Evidence aggregates to a predominantly nuclear/pre-60S association, consistent with a role in late nucleoplasmic steps and nuclear export of the large subunit. Tma16 is referenced as nuclear-localized in pre-60S assembly factor discussions (https://doi.org/10.7554/eLife.52474; 7 Jan 2020) (purnima2020thegtpasenog1 pages 1-3) and appears in the pre-60S export accessory list in human live-cell work (https://doi.org/10.1016/j.isci.2023.107445; 18 Aug 2023) (junod2023dynamicsofnuclear pages 6-10).
- Stage of ribosome biogenesis: The linkage to pre-60S export/maturation steps (alongside eIF6, NMD3) places TMA16 late in the large subunit assembly trajectory, near or during nuclear export and early cytoplasmic maturation (https://doi.org/10.1016/j.isci.2023.107445; 18 Aug 2023) (junod2023dynamicsofnuclear pages 6-10). Structural work on Drg1-mediated Rlp24 removal and Nog1-dependent steps provides the mechanistic context into which Tma16 is placed, albeit with limited direct structural detail (https://doi.org/10.1038/s41594-022-00832-5; 12 Sep 2022) (prattes2022visualizingmaturationfactor pages 7-8); (https://doi.org/10.7554/eLife.52474; 7 Jan 2020) (purnima2020thegtpasenog1 pages 1-3).
- Molecular function: The collective evidence supports classification as a ribosome-associated factor (RAF) or export adapter in the pre-60S pathway, not as an enzyme or transporter. It likely functions as an accessory component facilitating ribosomal subunit export or maturation checkpoint transitions, consistent with its co-listing among eIF6 and NMD3 (https://doi.org/10.1016/j.isci.2023.107445; 18 Aug 2023) (junod2023dynamicsofnuclear pages 6-10) and its mention as a nuclear-localized, structurally under-characterized assembly factor (https://doi.org/10.1038/s41594-022-00832-5; 12 Sep 2022) (prattes2022visualizingmaturationfactor pages 7-8); (https://doi.org/10.7554/eLife.52474; 7 Jan 2020) (purnima2020thegtpasenog1 pages 1-3).
- Particle association and interactions: Human evidence favors pre-60S association (eIF6, NMD3, LLPH co-mention with TMA16) (https://doi.org/10.1016/j.isci.2023.107445; 18 Aug 2023) (junod2023dynamicsofnuclear pages 6-10). Independent analyses of translation initiation networks (EIF4G2) also list TMA16 among assembly factors, implying connectivity to translation initiation machinery (https://doi.org/10.26508/lsa.202302338; 2 Dec 2024) (meril2024lossoffunctioncancerlinkedmutations pages 7-8). Foundational yeast studies embed Tma16 within ribosome-associated proteomes (https://doi.org/10.1101/gad.1422006; 22 May 2006) (fleischer2006systematicidentificationand pages 7-8). Direct binary interactions for human TMA16 remain sparsely resolved in the cited works.
- Structural observations: Cryo-EM studies report only weak density for Tma16 at the mammalian pre-60S site and note a general lack of structural information for Tma16 on pre-60S, indicating that its exact binding mode and interfaces remain to be precisely defined (https://doi.org/10.1038/s41594-022-00832-5; 12 Sep 2022) (prattes2022visualizingmaturationfactor pages 7-8). This cautions against over-specifying binding partners without further primary structural evidence.
- RQC/translation stress networks: While direct RQC assignment for TMA16 is not established in the human-focused sources above, yeast replication stress work implicates TMA16 (mRNA) among P-body-regulated targets, and authors annotate TMA16 and RRS1 as ribosome-associated genes affected under stress, linking TMA16 to mRNA fate pathways under genotoxic stress (https://doi.org/10.1038/s41467-017-00632-2; 22 Sep 2017) (lollkrippleber2017pbodyproteinsregulate pages 7-8). This supports a model where TMA16 expression may be tuned by RNA granule pathways under stress, indirectly connecting it to translation quality control.

Disease associations and translational relevance
- Cancer/biomarker context: Current human data show detection of TMA16 in cancer proteome fractions (unfoldome) but do not yet substantiate a robust biomarker or therapeutic association; it was not included in the interactome network of that 2024 study (https://doi.org/10.3390/ijms25031552; 26 Jan 2024) (paromov2024theproteomicanalysis pages 1-2). The EIF4G2 cancer study providing interaction landscape mentions TMA16 among assembly factors, suggesting indirect relevance to translation alterations in tumors, but without TMA16-focused functional oncology data (https://doi.org/10.26508/lsa.202302338; 2 Dec 2024) (meril2024lossoffunctioncancerlinkedmutations pages 7-8). Thus, disease linkage remains preliminary and inferential.

Limitations and open questions
- Direct biochemical function and high-resolution structure for human TMA16 on pre-60S remain incompletely defined; cryo-EM studies note weak or unassigned density and lack of detailed positioning. Additional proteomics, interaction mapping, and structural work (focused on human pre-60S particles) will be needed to firmly place TMA16 within specific export or maturation checkpoints (https://doi.org/10.1038/s41594-022-00832-5; 12 Sep 2022) (prattes2022visualizingmaturationfactor pages 7-8); (https://doi.org/10.7554/eLife.52474; 7 Jan 2020) (purnima2020thegtpasenog1 pages 1-3).

Mandatory verification summary
- Gene symbol and protein match: TMA16 (human) corresponds to translation machinery-associated protein 16, UniProt Q96EY4, consistent with database and recent proteomics mentions (https://doi.org/10.3390/ijms25031552; 26 Jan 2024) (paromov2024theproteomicanalysis pages 1-2).
- Organism: Homo sapiens; all primary recent data cited for identity and accessory lists are human studies (iScience 2023; Life Sci Alliance 2024; IJMS 2024) (junod2023dynamicsofnuclear pages 6-10, meril2024lossoffunctioncancerlinkedmutations pages 7-8, paromov2024theproteomicanalysis pages 1-2).
- Domains/family alignment: Belongs to the TMA16 family; literature consistently refers to Tma16 as a ribosome-associated factor in eukaryotes; no conflict detected (fleischer2006systematicidentificationand pages 7-8, purnima2020thegtpasenog1 pages 1-3).
- Ambiguity check: No conflicting gene/protein with the TMA16 symbol was used; instances referring to yeast Tma16 are used only for comparative inference and pathway context.

References (URLs and dates)
- Paromov V et al. The Proteomic Analysis of Cancer-Related Alterations in the Human Unfoldome. Int J Mol Sci. Published 26 Jan 2024. https://doi.org/10.3390/ijms25031552 (paromov2024theproteomicanalysis pages 1-2).
- Junod SL et al. Dynamics of nuclear export of pre-ribosomal subunits… iScience. Published 18 Aug 2023. https://doi.org/10.1016/j.isci.2023.107445 (junod2023dynamicsofnuclear pages 6-10).
- Prattes M et al. Visualizing maturation factor extraction… Nat Struct Mol Biol. Published 12 Sep 2022. https://doi.org/10.1038/s41594-022-00832-5 (prattes2022visualizingmaturationfactor pages 7-8, prattes2022visualizingmaturationfactor pages 10-11).
- Klingauf-Nerurkar P et al. The GTPase Nog1 co-ordinates… eLife. Published 7 Jan 2020. https://doi.org/10.7554/eLife.52474 (purnima2020thegtpasenog1 pages 1-3).
- Meril S et al. Loss-of-function cancer-linked mutations in EIF4G2… Life Sci Alliance. Published 2 Dec 2024. https://doi.org/10.26508/lsa.202302338 (meril2024lossoffunctioncancerlinkedmutations pages 7-8).
- Loll-Krippleber R, Brown GW. P-body proteins regulate transcriptional rewiring… Nat Commun. Published 22 Sep 2017. https://doi.org/10.1038/s41467-017-00632-2 (lollkrippleber2017pbodyproteinsregulate pages 7-8).
- Fleischer TC et al. Systematic identification and functional screens… Genes Dev. Published 22 May 2006. https://doi.org/10.1101/gad.1422006 (fleischer2006systematicidentificationand pages 7-8).

Citations: Paromov 2024 (paromov2024theproteomicanalysis pages 1-2); Junod 2023 (junod2023dynamicsofnuclear pages 6-10); Prattes 2022 (prattes2022visualizingmaturationfactor pages 7-8, prattes2022visualizingmaturationfactor pages 10-11); Klingauf-Nerurkar 2020 (purnima2020thegtpasenog1 pages 1-3); Meril 2024 (meril2024lossoffunctioncancerlinkedmutations pages 7-8); Loll-Krippleber 2017 (lollkrippleber2017pbodyproteinsregulate pages 7-8); Fleischer 2006 (fleischer2006systematicidentificationand pages 7-8).

References

1. (paromov2024theproteomicanalysis pages 1-2): Victor Paromov, Vladimir N. Uversky, Ayorinde Cooley, Lincoln E. Liburd, Shyamali Mukherjee, Insung Na, Guy W. Dayhoff, and Siddharth Pratap. The proteomic analysis of cancer-related alterations in the human unfoldome. International Journal of Molecular Sciences, 25:1552, Jan 2024. URL: https://doi.org/10.3390/ijms25031552, doi:10.3390/ijms25031552. This article has 4 citations and is from a poor quality or predatory journal.

2. (purnima2020thegtpasenog1 pages 1-3): Purnima Klingauf-Nerurkar, Ludovic C. Gillet, Daniela Portugal-Calisto, Michaela Oborska-Oplova, Martin Jäger, Olga T. Schubert, Agnese Pisano, Cohue Peña, Sanjana Rao, Martin Altvater, Yiming Chang, Ruedi Aebersold, and Vikram G. Panse. The gtpase nog1 co-ordinates the assembly, maturation and quality control of distant ribosomal functional centers. eLife, Jan 2020. URL: https://doi.org/10.7554/elife.52474, doi:10.7554/elife.52474. This article has 52 citations and is from a domain leading peer-reviewed journal.

3. (prattes2022visualizingmaturationfactor pages 7-8): Michael Prattes, Irina Grishkovskaya, Victor-Valentin Hodirnau, Christina Hetzmannseder, Gertrude Zisser, Carolin Sailer, Vasileios Kargas, Mathias Loibl, Magdalena Gerhalter, Lisa Kofler, Alan J. Warren, Florian Stengel, David Haselbach, and Helmut Bergler. Visualizing maturation factor extraction from the nascent ribosome by the aaa-atpase drg1. Nature Structural & Molecular Biology, 29:942-953, Sep 2022. URL: https://doi.org/10.1038/s41594-022-00832-5, doi:10.1038/s41594-022-00832-5. This article has 18 citations and is from a highest quality peer-reviewed journal.

4. (junod2023dynamicsofnuclear pages 6-10): Samuel L. Junod, Mark Tingey, Joseph M. Kelich, Alexander Goryaynov, Karl Herbine, and Weidong Yang. Dynamics of nuclear export of pre-ribosomal subunits revealed by high-speed single-molecule microscopy in live cells. iScience, 26:107445, Aug 2023. URL: https://doi.org/10.1016/j.isci.2023.107445, doi:10.1016/j.isci.2023.107445. This article has 6 citations and is from a peer-reviewed journal.

5. (meril2024lossoffunctioncancerlinkedmutations pages 7-8): Sara Meril, Marcela Bahlsen, Miriam Eisenstein, Alon Savidor, Yishai Levin, Shani Bialik, Shmuel Pietrokovski, and Adi Kimchi. Loss-of-function cancer-linked mutations in the eif4g2 non-canonical translation initiation factor. Life Science Alliance, 7:e202302338, Dec 2024. URL: https://doi.org/10.26508/lsa.202302338, doi:10.26508/lsa.202302338. This article has 3 citations and is from a peer-reviewed journal.

6. (kanwal2023analysisofmultifunctional pages 67-71): Nidhi Kanwal. Analysis of multifunctional rna helicase regulation by protein cofactors in different gene expression processes. ArXiv, 2023. URL: https://doi.org/10.53846/goediss-10092, doi:10.53846/goediss-10092. This article has 0 citations.

7. (lollkrippleber2017pbodyproteinsregulate pages 7-8): Raphael Loll-Krippleber and Grant W. Brown. P-body proteins regulate transcriptional rewiring to promote dna replication stress resistance. Nature Communications, Sep 2017. URL: https://doi.org/10.1038/s41467-017-00632-2, doi:10.1038/s41467-017-00632-2. This article has 50 citations and is from a highest quality peer-reviewed journal.

8. (fleischer2006systematicidentificationand pages 7-8): Tracey C. Fleischer, Connie M. Weaver, K. Jill McAfee, Jennifer L. Jennings, and Andrew J. Link. Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes. Genes & development, 20 10:1294-307, May 2006. URL: https://doi.org/10.1101/gad.1422006, doi:10.1101/gad.1422006. This article has 385 citations and is from a highest quality peer-reviewed journal.

9. (prattes2022visualizingmaturationfactor pages 10-11): Michael Prattes, Irina Grishkovskaya, Victor-Valentin Hodirnau, Christina Hetzmannseder, Gertrude Zisser, Carolin Sailer, Vasileios Kargas, Mathias Loibl, Magdalena Gerhalter, Lisa Kofler, Alan J. Warren, Florian Stengel, David Haselbach, and Helmut Bergler. Visualizing maturation factor extraction from the nascent ribosome by the aaa-atpase drg1. Nature Structural & Molecular Biology, 29:942-953, Sep 2022. URL: https://doi.org/10.1038/s41594-022-00832-5, doi:10.1038/s41594-022-00832-5. This article has 18 citations and is from a highest quality peer-reviewed journal.

Citations

1. paromov2024theproteomicanalysis pages 1-2
2. prattes2022visualizingmaturationfactor pages 7-8
3. junod2023dynamicsofnuclear pages 6-10
4. meril2024lossoffunctioncancerlinkedmutations pages 7-8
5. kanwal2023analysisofmultifunctional pages 67-71
6. lollkrippleber2017pbodyproteinsregulate pages 7-8
7. fleischer2006systematicidentificationand pages 7-8
8. prattes2022visualizingmaturationfactor pages 10-11
9. https://doi.org/10.3390/ijms25031552
10. https://doi.org/10.7554/eLife.52474
11. https://doi.org/10.1038/s41594-022-00832-5
12. https://doi.org/10.1016/j.isci.2023.107445
13. https://doi.org/10.1101/gad.1422006
14. https://doi.org/10.3390/ijms25031552;
15. https://doi.org/10.1101/gad.1422006;
16. https://doi.org/10.1016/j.isci.2023.107445;
17. https://doi.org/10.1038/s41594-022-00832-5;
18. https://doi.org/10.26508/lsa.202302338;
19. https://doi.org/10.7554/eLife.52474;
20. https://doi.org/10.1038/s41467-017-00632-2;
21. https://doi.org/10.26508/lsa.202302338
22. https://doi.org/10.1038/s41467-017-00632-2
23. https://doi.org/10.3390/ijms25031552,
24. https://doi.org/10.7554/elife.52474,
25. https://doi.org/10.1038/s41594-022-00832-5,
26. https://doi.org/10.1016/j.isci.2023.107445,
27. https://doi.org/10.26508/lsa.202302338,
28. https://doi.org/10.53846/goediss-10092,
29. https://doi.org/10.1038/s41467-017-00632-2,
30. https://doi.org/10.1101/gad.1422006,

Introduction and Gene Identity: The human TMA16 gene (Translation Machinery Associated 16, UniProt Q96EY4) encodes a small, 203-amino-acid protein that is conserved across eukaryotes (pmc.ncbi.nlm.nih.gov). It was originally identified in yeast (S. cerevisiae) as an uncharacterized protein associated with ribosomes (pmc.ncbi.nlm.nih.gov) and is also known by aliases such as C4orf43 (chromosome 4 open reading frame 43) and UPF0534 protein C4orf43 (www.genecards.org). TMA16 belongs to a eukaryote-specific protein family (Pfam PF11176) and has no bacterial homologs, indicating it evolved to assist the complex process of eukaryotic ribosome assembly. Importantly, TMA16 is not a ribosomal protein itself; rather, it functions as a ribosome assembly factor – one of the ~200 trans-acting factors that bind pre-ribosomal particles during maturation but do not become part of the final ribosome (pmc.ncbi.nlm.nih.gov). According to curated database annotations, TMA16 “enables preribosome binding activity” and is involved in 60S ribosomal subunit biogenesis, operating within the cell nucleus (localized to the nucleolus and nucleoplasm) (www.ncbi.nlm.nih.gov). In brief, TMA16 is a trans-acting helper protein required for building the large ribosomal subunit in human cells (www.genecards.org).

Role in 60S Ribosomal Subunit Biogenesis: Current understanding places TMA16 as a late-acting assembly factor that facilitates the maturation and nuclear export of the 60S subunit (the large subunit of the human ribosome). The 60S subunit contains the 5S, 5.8S, and 28S rRNAs and ~47 ribosomal proteins, and its assembly in the nucleus is a stepwise process requiring many helper proteins. TMA16’s primary function is to bind to immature 60S particles (pre-60S ribosomes) and aid their final maturation. A Swiss-Prot summary for human TMA16 notes that it is “involved in the biogenesis of the 60S ribosomal subunit in the nucleus” (www.genecards.org). More specifically, TMA16 appears to act by physically attaching to the pre-ribosome and stabilizing critical rRNA structures during the late stages of assembly. This is supported by gene ontology annotations that TMA16 binds preribosomal complexes and by its experimentally observed location on nascent 60S particles (www.ncbi.nlm.nih.gov).

Structural Insights (Cryo-EM Studies 2020–2023): Until recently, TMA16 was poorly characterized. However, breakthrough cryo-electron microscopy (cryo-EM) studies in the last few years have visualized TMA16 directly on assembling human ribosomes, revealing its location and interactions at near-atomic detail. A 2020 study in Nature Communications examined structures of human pre-60S particles and discovered a previously unknown factor bound to them; this factor was identified as TMA16 (pmc.ncbi.nlm.nih.gov). In those cryo-EM maps, TMA16 is seen wedged between the 5S ribonucleoprotein (5S RNP) (a complex of the 5S rRNA with ribosomal proteins L5 and L11 in the large subunit’s “central protuberance”) and the P0 stalk base of the large subunit (pmc.ncbi.nlm.nih.gov). In other words, TMA16 sits in a pocket on the pre-60S particle, occupying the space between the rotated 5S rRNA and the base of ribosomal protein P0 (which anchors the stalk that binds translation factors) (pmc.ncbi.nlm.nih.gov).

Identification of TMA16 in these structures was confirmed by cross-linking mass spectrometry (CXMS) evidence: the cryo-EM study reported a cross-link between lysine 114 of TMA16 and lysine 136 of ribosomal protein L18a (uL18) (pmc.ncbi.nlm.nih.gov), a physical contact that could only occur if the mystery protein was positioned on the pre-60S. This cross-link, together with the protein’s size and shape in the density map, allowed researchers to assign the density to TMA16 (pmc.ncbi.nlm.nih.gov). They built an atomic model for TMA16 (residues 17–166 of the 203 aa chain were resolved) bound to the pre-60S (pmc.ncbi.nlm.nih.gov). The model revealed that TMA16 is largely α-helical and uses an extended N-terminal helix to engage the ribosome. Notably, a long N-terminal helix (residues ~19–60) of TMA16 protrudes into the pre-60S particle, reaching ~60 Å in length (pmc.ncbi.nlm.nih.gov). This helix inserts alongside the rRNA and makes multiple contacts: researchers observed that conserved basic residues on TMA16 directly contact ribosomal RNA nucleotides (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). For example, Histidine 18 and Arginine 22 of TMA16 form specific interactions with bases A1867 and G1864 in helix 39 of the 28S rRNA (pmc.ncbi.nlm.nih.gov). At the same time, the TMA16 helix is positioned against the 5S rRNA, interacting via several positively charged residues (pmc.ncbi.nlm.nih.gov). These multi-point contacts underscore TMA16’s role as an rRNA-binding assembly factor or “rRNA chaperone.” By binding simultaneously to the 5S rRNA and a region of the 28S rRNA (helix 39 and nearby helices), TMA16 bridges different parts of the ribosome. Its positioning was seen to cause a slight distortion (a deflection of a few Ångströms) in helix 39 of the rRNA – essentially TMA16 wedges into the particle and stabilizes a particular rRNA conformation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This is significant because during 60S maturation, the 5S RNP must rotate into its final position and several rRNA helices (like H39, H42, etc.) undergo remodeling; TMA16 appears to sense and perhaps promote the correct conformational changes in this region (pmc.ncbi.nlm.nih.gov).

Crucially, TMA16’s strategic location and contacts suggest a role in preparing the pre-60S for nuclear export. In the 2020 cryo-EM structures, TMA16 is present in “late nuclear” ribosome assembly intermediates – specifically, particles just after the loading of the essential export adapter NMD3 (which binds pre-60S to facilitate export) (pmc.ncbi.nlm.nih.gov). TMA16 itself does not appear in earlier-state particles, but only after the 5S RNP has rotated into place and NMD3 and the GTP-binding protein GTPBP4 (human homolog of yeast Nog1) are bound (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Given this timing, the authors proposed that TMA16 may function as an additional nuclear export factor or adapter that helps stabilize the pre-60S particle for transport to the cytoplasm (pmc.ncbi.nlm.nih.gov). The idea is that TMA16, by bridging the 5S RNP and nearby rRNA, might lock the structure in a state compatible with export through the nuclear pore. Supporting this notion, proteomic studies have found TMA16 in complex with known 60S export machinery. For example, a 2015 deep proteomics survey of CRM1 (XPO1) cargoes identified TMA16 among the proteins that interact with the Crm1 export pathway (pmc.ncbi.nlm.nih.gov). (Crm1 is the export receptor that recognizes NMD3; TMA16’s association with Crm1-containing complexes suggests it hitches a ride or contributes to the export of pre-60S subunits.)

Function and Interactions in the Assembly Pathway: TMA16 can be viewed as a late-stage 60S assembly factor that transiently binds pre-ribosomes and is released once its job is done. Its binding must be precisely timed within the assembly pathway. Structural analyses indicate that TMA16’s binding site on the pre-60S overlaps or clashes with some earlier assembly factors, meaning those factors must disassemble before TMA16 can bind (pmc.ncbi.nlm.nih.gov). Indeed, a recent 2023 study (Cell Research, 2023) that visualized even later nuclear assembly states found that TMA16 only appears after factors like NLE1 and CCDC86 have left the particle (pmc.ncbi.nlm.nih.gov). TMA16 also shares part of its binding region with NMD3 (the major export adaptor), implying a coordinated handoff or co-occupation: the late pre-60S can accommodate NMD3 together with TMA16, but as maturation proceeds, these factors will depart in sequence (pmc.ncbi.nlm.nih.gov). Once the pre-60S is ready for export and subsequent cytoplasmic maturation, TMA16 itself must be released – its position is incompatible with certain final remodeling events, so it cannot remain bound indefinitely (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Experimental evidence confirms that TMA16’s attachment to pre-ribosomes is temporary and tightly regulated. In the cryo-EM series, TMA16 was present in specific intermediate states (“State A” in the 2020 study) but was absent from more mature states (States B and C) (pmc.ncbi.nlm.nih.gov), indicating it naturally dissociates as the particle matures. Moreover, blocking upstream steps causes TMA16 to accumulate aberrantly, highlighting its normal point of action. In yeast, for example, if the release of an upstream factor (Nog1, a GTPase in an earlier step) is genetically impaired, the yeast Tma16 protein builds up on stalled pre-60S particles (pmc.ncbi.nlm.nih.gov). Normally, Nog1 (human GTPBP4) is removed from the nascent 60S by an ATPase Drg1, allowing later factors to bind; if Nog1 fails to come off, Tma16 cannot progress and remains stuck (pmc.ncbi.nlm.nih.gov). This observation (from recent yeast genetics research) supports a model where TMA16 acts after Nog1/GTPBP4 function and likely before the final large subunit export and cytoplasmic maturation steps.

Once the pre-60S is exported to the cytoplasm, any remaining assembly factors must be removed so the subunit can participate in translation. Yeast studies show that Tma16 interacts with Rei1, a cytoplasmic 60S maturation factor (pmc.ncbi.nlm.nih.gov). Rei1 is known to bind pre-60S particles in the cytoplasm and help release certain nuclear export factors (like the shuttling protein Arx1). Cross-linking data revealed Tma16’s N-terminus contacts Rei1, and simultaneously Tma16’s C-terminus contacts ribosomal protein uL18 on the 60S (pmc.ncbi.nlm.nih.gov). This positioning suggests that in cytoplasmic 60S intermediates, Rei1 may directly engage Tma16 to trigger its dissociation. Consistent with this, the abundance pattern of Tma16 during purification of assembly intermediates in yeast closely mirrored that of the Arx1–Alb1 complex, which is a known nuclear export factor complex for the 60S (pmc.ncbi.nlm.nih.gov). Tma16 was enriched in late 60S particles (including those bound by Arx1 and by Lsg1 – a cytoplasmic factor for final 60S tuning), but not in very early ones (pmc.ncbi.nlm.nih.gov). Researchers concluded that Tma16 joins the pre-60S in the nucleus together with (or just after) the Arx1/Alb1 loading, travels with the particle to the cytoplasm, and is then removed there (pmc.ncbi.nlm.nih.gov). In other words, TMA16 functions analogously to a shuttling maturation factor that escorts the subunit through the nuclear pore and then hands it off to cytoplasmic factors.

Complex Formation with L10K (C19orf53): One of the latest developments (2023) in understanding TMA16 came from an even higher-resolution look at human pre-60S particles. In a late-stage pre-60S structure, TMA16 was found to partner with another small protein called C19orf53, also known as L10K (Leydig cell tumor 10 kDa protein homolog) (pmc.ncbi.nlm.nih.gov). L10K was an uncharacterized factor (10 kDa in size) that co-occupies the pre-60S at the final steps of nuclear maturation. The cryo-EM data showed that L10K binds adjacent to TMA16, and the two form a tight complex on the ribosome surface (pmc.ncbi.nlm.nih.gov). Specifically, L10K consists of a single helix with flexible loops, and this helix packs against TMA16’s helix in a hydrophobic interface (pmc.ncbi.nlm.nih.gov). The TMA16–L10K two-helix bundle encircles a segment of 28S rRNA (helix 89) in cooperation with GTPBP4 (pmc.ncbi.nlm.nih.gov). This three-factor cluster (TMA16, L10K, and GTPBP4) appears to clasp around rRNA helix 89, stabilizing it similarly to how another assembly factor (SDAD1) stabilizes a different rRNA helix in an earlier state (pmc.ncbi.nlm.nih.gov). The discovery of L10K partnering with TMA16 is a prime example of how multiple dedicated factors act together as rRNA chaperones: they locally confine and mold specific rRNA helices to ensure proper folding (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Importantly, the binding of TMA16/L10K requires that earlier factors (like NLE1 and CCDC86) have been released from the particle (pmc.ncbi.nlm.nih.gov). Once those are gone, TMA16 and L10K co-recruit to the site. Thus, TMA16 doesn’t act alone; it forms part of a late-assembly “checkpoint” complex with L10K (and likely GTPBP4 and others) that locks in the final rRNA architecture before the subunit is deemed export-competent (pmc.ncbi.nlm.nih.gov). This late complex is short-lived: after stabilizing the particle and facilitating the final rRNA arrangements, TMA16 and L10K both depart (neither is present in the fully mature 60S subunit). The coordinated release of these factors is one of the last steps before the large subunit joins the small subunit in the cytoplasm to form a functional ribosome.

Cellular Localization and Biochemical Pathway: In line with its role in ribosome biogenesis, TMA16 operates in the cell nucleus, where ribosomal subunits are assembled. High-throughput localization studies and curated annotations place TMA16 in the nucleolus (the site of rRNA transcription and early ribosome assembly) and the nucleoplasm (where later assembly steps occur) (www.ncbi.nlm.nih.gov). This distribution suggests TMA16 might shuttle or be present throughout the nucleus – possibly being recruited to pre-ribosomes as they transition from the nucleolus to nucleoplasm. Indeed, late 60S assembly (when TMA16 acts) typically occurs at the nucleoplasm/nuclear periphery, just before export. TMA16’s presence in the nucleolus could indicate it is synthesized and concentrated there, or that a fraction associates with particles still in nucleoli; however, its main functional engagement appears when pre-60S particles reach a more mature stage in the nucleoplasm. Consistent with being a ribosome assembly factor, TMA16 would be expected to colocalize with nucleolar/ribosomal markers and to leave the nucleus only bound to pre-60S particles. Once those particles export and shed their factors, TMA16 likely recycles back to the nucleus (similar to how NMD3 and other export factors shuttle back).

Biochemically, TMA16 is part of the ribosome assembly pathway, specifically the pathway of 60S subunit maturation. It does not act in isolation but interacts with numerous other assembly factors: for instance, as noted, it contacts GTPBP4 (Nog1), NMD3, Lsg1, Rei1, Arx1, ZNF593, and others in various stages (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov) (string-db.org). These interactions integrate TMA16 into the large network of ribosome biogenesis. Functionally, TMA16 doesn’t catalyze a chemical reaction (it is not an enzyme); rather, it serves a structural/regulatory role, ensuring that certain structural rearrangements in the pre-rRNA occur and that the pre-60S is competent for export. In terms of signaling pathways, ribosome assembly factors like TMA16 can be targets of cellular surveillance pathways – for example, if ribosome assembly fails (due to loss of TMA16 or others), cells activate a p53-dependent nucleolar stress response (pmc.ncbi.nlm.nih.gov). However, TMA16 itself is not known to be a signaling molecule; its role is confined to the biogenesis pathway of the ribosome, which is a fundamental biosynthetic process in the cell.

Evolutionary Conservation: The function of TMA16 appears to be ancient and conserved among eukaryotes. The very name “TMA16 homolog (S. cerevisiae)” in the human gene description highlights that yeast and human TMA16 are orthologs. Back in 2006, when the yeast protein Tma16 was first described, bioinformatics searches found putative TMA16 counterparts in insects, worms, plants, rodents, and humans (pmc.ncbi.nlm.nih.gov). Although the sequence similarity is modest (the short length and low complexity of the protein made E-values relatively high in those alignments), the presence of TMA16 across all these lineages suggests a conserved functional requirement (pmc.ncbi.nlm.nih.gov). Indeed, later experimental work has validated that yeast Tma16 and human TMA16 occupy equivalent positions on the pre-60S and likely perform analogous roles (pmc.ncbi.nlm.nih.gov). Key residues (like the aforementioned H18/R22 in human) are conserved in yeast, indicating that the rRNA-binding interface is under evolutionary constraint (pmc.ncbi.nlm.nih.gov). This conservation also extends to interactions: yeast Tma16 interacts genetically or physically with yeast Crm1 (exportin) and Rei1, just as human TMA16 interacts with XPO1 and has a presumed Rei1-like pathway (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The evolutionary retention of TMA16 in organisms from yeast to humans underscores that its role in ribosome biogenesis is fundamental. Not all ribosome assembly factors are universally conserved – some are specific to yeast or to metazoans – but TMA16 is one of those factors that appear to be present in all eukaryotes, implying the aspect of subunit maturation it participates in is a common, necessary step.

It is worth noting that TMA16 is an essential or vital gene in many contexts. In yeast, genome-wide studies have classified most ribosome biogenesis factors (including TMA16) as important for viability or optimal growth. While a yeast ∆tma16 deletion strain is viable in rich media (indicating Tma16 is not absolutely essential under standard conditions), it shows phenotypes under stress, and the cells grow more slowly (pmc.ncbi.nlm.nih.gov). In human cells, large-scale CRISPR/Cas9 knockout screens (such as those in the Cancer DepMap project) typically find that ribosome assembly factors are among the most critical genes for cell proliferation. Although specific CRISPR essentiality data for TMA16 were not detailed in literature, it can be inferred that loss of TMA16 would severely impair 60S production and cell growth, likely triggering p53-mediated apoptosis if p53 is intact (a common outcome of nucleolar disruption) (pmc.ncbi.nlm.nih.gov). This conjecture aligns with the fact that no inherited diseases have been reported for TMA16 mutations – a strong loss-of-function might be embryonic lethal, whereas milder variants have not yet been linked to a distinct disorder.

Biological and Medical Significance: Ribosome biogenesis is a process of keen interest in cell biology and medicine. Dysregulation of ribosome production is linked to disease: for example, a class of developmental disorders known as ribosomopathies are caused by mutations in ribosomal proteins or assembly factors (pmc.ncbi.nlm.nih.gov). Patients with ribosomopathies (such as Diamond-Blackfan anemia or Shwachman-Diamond syndrome) have defects in making ribosomes, leading to tissue-specific problems and a predisposition to cancer (pmc.ncbi.nlm.nih.gov). While no ribosomopathy is currently attributed to TMA16, this is possibly because TMA16 has not been found mutated in patient populations – it may be essential, as noted, or its mutations are very rare. Nonetheless, understanding TMA16’s function helps complete the picture of how large subunits are built, which is directly relevant to these diseases. For instance, if a patient had a mutation in TMA16 that reduces its function, one would predict a large subunit biogenesis defect (perhaps causing accumulation of unexported pre-60S in the nucleus, nucleolar stress, and downstream consequences). As genomic sequencing becomes more widespread, it is not implausible that future studies might identify individuals or cancer cells with TMA16 mutations, given the critical role of this protein.

In the context of cancer biology, ribosome biogenesis factors like TMA16 are gaining attention. Cancer cells typically ramp up ribosome production to support rapid growth, and in some cases they become “addicted” to this increased biogenesis. Evidence has emerged that dysfunctional ribosome assembly can contribute to oncogenesis or that cancer cells are selectively sensitive to perturbations in ribosome assembly (pmc.ncbi.nlm.nih.gov). A recent review by Pelletier et al. (2023) emphasizes that ribosome biogenesis and cancer are intimately connected, with many tumors showing overactive nucleoli and assembly factor dysregulation (pmc.ncbi.nlm.nih.gov). Consequently, targeting ribosome biogenesis is being explored as a therapeutic strategy (pmc.ncbi.nlm.nih.gov). Small-molecule inhibitors of rRNA synthesis (like CX-5461) or of nucleolar enzymes have entered clinical trials for cancer. Though there are no drugs targeting TMA16 specifically, one could conceptually consider that inhibiting a factor like TMA16 might slow 60S subunit production and thus protein synthesis in rapidly dividing cells. Any such approach would need to balance toxicity to normal cells, since ribosome assembly is essential in healthy tissues as well. However, the general principle is that certain assembly steps might be targetable “choke points” in cancer – and late-stage factors such as TMA16 could be of interest if tumor cells are more reliant on high ribosome output than normal cells.

From a research and “real-world” standpoint, the elucidation of TMA16’s role provides a new biomarker and potential handle for studying nucleolar stress. For example, the presence or absence of TMA16 on pre-ribosomes could be used experimentally to define the stage of ribosome assembly being affected by a drug or mutation. Its interactions (with GTPBP4, NMD3, L10K, etc.) form a network that can be probed to understand how assembly is coordinated. There are also biotechnological implications: proteins like TMA16, which bind specifically to pre-rRNA, could in theory be used to isolate late ribosome assembly intermediates or to develop assays for ribosome assembly activity in extracts. Indeed, the 2022 comprehensive study of 60S biogenesis factors used TMA16 as a handle (via epitope-tagging) to purify and analyze late 60S particles in yeast (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

In summary, TMA16 is a key player in the final stages of building the large ribosomal subunit. It acts within the nucleus to bind and stabilize the near-mature 60S precursors, working alongside other factors to ensure the subunit is correctly folded and ready for export. It then dissociates (likely in the cytoplasm) to allow completion of ribosome assembly. Discovered only in the last two decades and characterized in detail in the last few years, TMA16 has transitioned from a “gene of unknown function” to a well-defined 60S ribosome assembly factor. This knowledge deepens our fundamental understanding of ribosome biogenesis – a central process of life – and may inform medical research, as defects in ribosome assembly are linked to disease. Ongoing studies continue to investigate TMA16’s precise regulatory mechanisms (e.g. how its release is triggered, whether it is regulated by phosphorylation or other modifications) and to explore whether it has any moonlighting roles outside ribosome assembly (so far, none are known). Given its conservation and critical function, TMA16 exemplifies how even small, previously overlooked proteins can play outsized roles in the cell’s core machinery. In the current state of research (2023–2024), TMA16 is recognized as an essential facilitator of ribosomal large subunit formation, operating as part of a tightly coordinated assembly pathway with no known direct enzymatic activity but indispensable scaffold and checkpoint functions (www.genecards.org) (pmc.ncbi.nlm.nih.gov).

References:

1. Liang et al., Nature Communications, July 15, 2020. “Structural snapshots of human pre-60S ribosomal particles before and after nuclear export.” (Cryo-EM study identifying TMA16 as a novel factor on late 60S; DOI: 10.1038/s41467-020-17237-x) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov)

2. Sailer et al., Cell Reports, Feb 8, 2022. “A comprehensive landscape of 60S ribosome biogenesis factors.” (Yeast study mapping assembly factor timing; confirms Tma16’s interactions with Rei1 and uL18 and its late joining of pre-60S; DOI: 10.1016/j.celrep.2022.110353) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov)

3. Ma et al. (Dong & Gao labs), Cell Research, July 25, 2023. “Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles.” (Higher-resolution cryo-EM of human 60S maturation; discovers TMA16–L10K complex encircling rRNA helix 89; DOI: 10.1038/s41422-023-00853-9) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov)

4. GeneCards/Human Genome/NCBI Gene (accessed 2025). TMA16 – Translation Machinery Associated 16 Homolog. (Database summary: “Enables preribosome binding activity. Involved in ribosomal large subunit biogenesis. Located in nucleolus and nucleoplasm.” – Alliance of Genome Resources, July 2025) (www.ncbi.nlm.nih.gov)

5. UniProt Knowledgebase (Swiss-Prot entry Q96EY4, last modified 2023). TMA16_HUMAN. (Protein entry: “Translation machinery-associated protein 16”; Function: involved in 60S ribosomal subunit biogenesis in the nucleus (www.genecards.org); notes protein family UPF0534 and synonyms C4orf43).

6. Fleischer et al., Genes & Development, May 15, 2006. “Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes.” (Yeast study that first named Tma16; shows conservation of TMA16 in eukaryotes (pmc.ncbi.nlm.nih.gov) and identified it in ribosome-bound fractions.)

7. Kirli et al., eLife, 2015. “A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning.” (Proteomic study of export complexes; reported interactions linking TMA16 to CRM1 export pathway (pmc.ncbi.nlm.nih.gov)).

8. STRING protein network for human TMA16 (functional partners prediction, accessed 2024) – highlights high-confidence interactions with GTPBP4 (Nog1), NMD3, and other ribosome biogenesis factors (string-db.org).

9. Kressler et al., Seminars in Cell & Dev. Biology, 2017. “Factors associated with ribosome biogenesis” – Review (background: ~200 assembly factors assist ribosome assembly; general principles of RBF function) (pmc.ncbi.nlm.nih.gov).

10. Pelletier et al., Seminars in Cell & Dev. Biology, 2023. “Ribosome biogenesis in cancer: new players and therapeutic avenues.” (Review on links between ribosome assembly and cancer; discusses how perturbing biogenesis – potentially including factors like TMA16 – could be exploited in therapy) (pmc.ncbi.nlm.nih.gov).

Citations

1. AnnotationURLCitation(end_index=335, start_index=191, title='Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1472904/#:~:text=Because%20the%20translation%20machinery%20is,At%20least%2067')
2. AnnotationURLCitation(end_index=591, start_index=447, title='A comprehensive landscape of 60S ribosome biogenesis factors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8884084/#:~:text=Of%20these%2C%20the%20most%20intriguing,We%20confirmed%20the')
3. AnnotationURLCitation(end_index=800, start_index=710, title='TMA16 Gene - GeneCards | TMA16 Protein | TMA16 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMA16#:~:text=,3')
4. AnnotationURLCitation(end_index=1395, start_index=1235, title='A comprehensive landscape of 60S ribosome biogenesis factors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8884084/#:~:text=Ribosome%20biogenesis%20is%20a%20complex%2C,RBFs%20are%20crucial%20for%20the')
5. AnnotationURLCitation(end_index=1783, start_index=1625, title='TMA16 translation machinery associated 16 homolog [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=55319#:~:text=Enables%20preribosome%20binding%20activity,Expression')
6. AnnotationURLCitation(end_index=2004, start_index=1899, title='TMA16 Gene - GeneCards | TMA16 Protein | TMA16 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMA16#:~:text=UniProtKB%2FSwiss')
7. AnnotationURLCitation(end_index=2753, start_index=2648, title='TMA16 Gene - GeneCards | TMA16 Protein | TMA16 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMA16#:~:text=UniProtKB%2FSwiss')
8. AnnotationURLCitation(end_index=3238, start_index=3080, title='TMA16 translation machinery associated 16 homolog [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=55319#:~:text=Enables%20preribosome%20binding%20activity,Expression')
9. AnnotationURLCitation(end_index=3859, start_index=3743, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=In%20the%20maps%20of%20states,2a')
10. AnnotationURLCitation(end_index=4259, start_index=4106, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=human%20factors%2C%20including%20an%20uncharacterized,assisted%20rRNA')
11. AnnotationURLCitation(end_index=4620, start_index=4467, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=human%20factors%2C%20including%20an%20uncharacterized,assisted%20rRNA')
12. AnnotationURLCitation(end_index=5054, start_index=4854, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=Facilitated%20by%20CXMS%2C%20which%20reported,helix%20%28residue%2019%E2%80%9360%2C%20~60%E2%80%89%C3%85%29%20points')
13. AnnotationURLCitation(end_index=5473, start_index=5282, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=match%20at%20L174%20Facilitated%20by,helix%20%28residue%2019%E2%80%9360%2C%20~60%E2%80%89%C3%85%29%20points')
14. AnnotationURLCitation(end_index=5785, start_index=5585, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=Facilitated%20by%20CXMS%2C%20which%20reported,helix%20%28residue%2019%E2%80%9360%2C%20~60%E2%80%89%C3%85%29%20points')
15. AnnotationURLCitation(end_index=6230, start_index=6030, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=Facilitated%20by%20CXMS%2C%20which%20reported,helix%20%28residue%2019%E2%80%9360%2C%20~60%E2%80%89%C3%85%29%20points')
16. AnnotationURLCitation(end_index=6523, start_index=6410, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=absence%20of%20TMA16,terminal')
17. AnnotationURLCitation(end_index=6648, start_index=6524, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=1,are%20further%20detailed%20in%20panels')
18. AnnotationURLCitation(end_index=6911, start_index=6787, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=1,are%20further%20detailed%20in%20panels')
19. AnnotationURLCitation(end_index=7147, start_index=7034, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=absence%20of%20TMA16,terminal')
20. AnnotationURLCitation(end_index=7742, start_index=7615, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=%28Fig,a%20mature%20conformation%20in%20the')
21. AnnotationURLCitation(end_index=7886, start_index=7743, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=region%20of%20TMA16,be%20important%20in%20stabilizing%20the')
22. AnnotationURLCitation(end_index=8289, start_index=8146, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=region%20of%20TMA16,be%20important%20in%20stabilizing%20the')
23. AnnotationURLCitation(end_index=8780, start_index=8635, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=TMA16%20is%20an%20uncharacterized%20nuclear,assembly%20factor')
24. AnnotationURLCitation(end_index=9092, start_index=8976, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=In%20the%20maps%20of%20states,2a')
25. AnnotationURLCitation(end_index=9244, start_index=9093, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=relied%20largely%20on%20side,in%20the%20equivalent%20positions%20as')
26. AnnotationURLCitation(end_index=9594, start_index=9437, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=of%20TMA16%20suggests%20that%20it,be%20important%20in%20stabilizing%20the')
27. AnnotationURLCitation(end_index=10162, start_index=9997, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=TMA16%20is%20conserved%20in%20eukaryotes,Very%20recently%2C%20yeast%20Tma16%20was')
28. AnnotationURLCitation(end_index=10945, start_index=10787, title='Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10624882/#:~:text=TMA16%2FL10K%2C%20and%20NMD3%20are%20successive,in%20the%20CP%20and%20the')
29. AnnotationURLCitation(end_index=11300, start_index=11142, title='Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10624882/#:~:text=TMA16%2FL10K%2C%20and%20NMD3%20are%20successive,in%20the%20CP%20and%20the')
30. AnnotationURLCitation(end_index=11717, start_index=11559, title='Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10624882/#:~:text=TMA16%2FL10K%2C%20and%20NMD3%20are%20successive,in%20the%20CP%20and%20the')
31. AnnotationURLCitation(end_index=12103, start_index=11933, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=close%20examination%20of%20the%20TMA16,observations%20suggest%20a%20relatively%20short')
32. AnnotationURLCitation(end_index=12250, start_index=12104, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=H39%20in%20state%20A%20is,a%20mature%20conformation%20in%20the')
33. AnnotationURLCitation(end_index=12671, start_index=12525, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=H39%20in%20state%20A%20is,a%20mature%20conformation%20in%20the')
34. AnnotationURLCitation(end_index=13170, start_index=13044, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=time%20window%20for%20TMA16%20action%3A,31')
35. AnnotationURLCitation(end_index=13478, start_index=13352, title='Structural snapshots of human pre-60S ribosomal particles before and after nuclear export - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7363849/#:~:text=time%20window%20for%20TMA16%20action%3A,31')
36. AnnotationURLCitation(end_index=14061, start_index=13921, title='A comprehensive landscape of 60S ribosome biogenesis factors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8884084/#:~:text=Tma16%20and%20Stm1%2C%20are%20also,ribosomal%20particles')
37. AnnotationURLCitation(end_index=14490, start_index=14350, title='A comprehensive landscape of 60S ribosome biogenesis factors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8884084/#:~:text=Tma16%20and%20Stm1%2C%20are%20also,ribosomal%20particles')
38. AnnotationURLCitation(end_index=15005, start_index=14844, title='A comprehensive landscape of 60S ribosome biogenesis factors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8884084/#:~:text=In%20our%20quantitative%20MS%20analysis%2C,and%20Rei1%20are%20located%20quite')
39. AnnotationURLCitation(end_index=15325, start_index=15164, title='A comprehensive landscape of 60S ribosome biogenesis factors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8884084/#:~:text=In%20our%20quantitative%20MS%20analysis%2C,and%20Rei1%20are%20located%20quite')
40. AnnotationURLCitation(end_index=15681, start_index=15520, title='A comprehensive landscape of 60S ribosome biogenesis factors - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8884084/#:~:text=In%20our%20quantitative%20MS%20analysis%2C,and%20Rei1%20are%20located%20quite')
41. AnnotationURLCitation(end_index=16320, start_index=16211, title='Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10624882/#:~:text=begins%20to%20depart,60S')
42. AnnotationURLCitation(end_index=16710, start_index=16569, title='Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10624882/#:~:text=helix%20of%20TMA16%2C%20and%20establishes,60S%20particle')
43. AnnotationURLCitation(end_index=16994, start_index=16853, title='Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10624882/#:~:text=helix%20of%20TMA16%2C%20and%20establishes,60S%20particle')
44. AnnotationURLCitation(end_index=17203, start_index=17102, title='Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10624882/#:~:text=N,Thus%2C%20this')
45. AnnotationURLCitation(end_index=17515, start_index=17414, title='Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10624882/#:~:text=N,Thus%2C%20this')
46. AnnotationURLCitation(end_index=17871, start_index=17728, title='Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10624882/#:~:text=as%20a%20means%20to%20guide,terminal%20domain%20of%20SDAD1')
47. AnnotationURLCitation(end_index=18013, start_index=17872, title='Visualizing the nucleoplasmic maturation of human pre-60S ribosomal particles - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10624882/#:~:text=helix%20of%20TMA16%2C%20and%20establishes,60S%20particle')
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