Falcon deep research report for human PEX16
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The deep research synthesis supplies the structural basis for reading PEX16's molecular function as adaptor/anchoring receptor activity rather than unqualified protein binding - a validated PEX3-binding loop with PEX19 engaging PEX3 on the opposite face.
"The authors propose a **trimeric complex** in which PEX16 anchors PEX3 at the peroxisomal membrane, while PEX19 binds PEX3 on the opposite face and can deliver PMPs"
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The PEX3-binding element of PEX16 is a defined cytosolic loop, which is the evidence cited in the core function description.
"PEX16 contains a large loop **(residues ~132–214)** predicted with high confidence to bind a pocket on PEX3"
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Combined Automated Annotation using Multiple IEA Methods
The membrane biogenesis peroxin Pex16p. Topogenesis and functional roles in peroxisomal membrane assembly.
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PEX16 membrane topology determined -- both N and C termini cytosolic, two transmembrane segments
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Residues 66-81 and first TM segment required for peroxisomal membrane integration
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Dysfunctional PEX16 variants interfere with PMP localization (Pex14p, Pex13p, PMP70)
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PEX16 C-terminal domain abrogates peroxisome restoration in pex3 and pex12 mutants
PEX19 is a predominantly cytosolic chaperone and import receptor for class 1 peroxisomal membrane proteins.
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PEX19 binds and stabilizes newly synthesized PMPs including PEX16 in the cytosol
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PEX16 contains two mPTS regions bound by PEX19 (aa 59-219 and aa 221-336)
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PEX19 functions as both chaperone and import receptor for class 1 PMPs
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Inhibition of PEX19 causes specific PMP import defect
Analysis of human Pex19p's domain structure by pentapeptide scanning mutagenesis.
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PEX19 carboxy-terminal domain interacts with PEX16 among other PMPs
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PEX19 has tripartite domain structure with PEX3-binding, PEX14-binding, and PMP-binding domains
Requirement for microtubules and dynein motors in the earliest stages of peroxisome biogenesis.
The origin and maintenance of mammalian peroxisomes involves a de novo PEX16-dependent pathway from the ER.
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PEX16 is cotranslationally inserted into the ER
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PEX16 traffics from ER to peroxisomes (photoactivation pulse-chase)
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PEX16 recruits PEX3 and PMP34 to ER membranes
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PEX16 with signal anchor sequence complements PEX16-deficient cells from ER
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New peroxisomes derive primarily from ER in growing cells
The peroxisomal membrane protein import receptor Pex3p is directly transported to peroxisomes by a novel Pex19p- and Pex16p-dependent pathway.
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PEX16 functions as the membrane receptor for PEX3-PEX19 complexes
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Ectopic PEX16 expression enhances PEX3 targeting 5-6 fold
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PEX16 knockdown abrogates PEX3 peroxisomal targeting
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PEX3 mPTS directly binds PEX16 (co-IP of cell-free synthesized proteins)
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Both N- and C-terminal regions of PEX16 indispensable for recruiting PEX3-PEX19 complexes
Pex3p-dependent peroxisomal biogenesis initiates in the endoplasmic reticulum of human fibroblasts.
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Pex3p requires Pex16p for ER location but not vice versa
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Pex3p follows ER-to-peroxisome route in mammalian cells
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De novo peroxisome biogenesis involves ER intermediate
Defining the membrane proteome of NK cells.
PEX14 is required for microtubule-based peroxisome motility in human cells.
Sec16B is involved in the endoplasmic reticulum export of the peroxisomal membrane biogenesis factor peroxin 16 (Pex16) in mammalian cells.
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Sec16B required for ER-to-peroxisome transport of PEX16
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Sec16B knockdown causes PEX16 redistribution to ER and peroxisome elongation
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PEX16 Sec16B-dependent trafficking links ER exit site machinery to peroxisome biogenesis
Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D.
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PEX16 identified as causative gene for CG-D (CG-IX) Zellweger syndrome
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PEX16 encodes 336 amino acid peroxisomal protein
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R176ter nonsense mutation found in patient
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PEX16 expression restores peroxisome biogenesis in CG-D patient fibroblasts
Peroxisome synthesis in the absence of preexisting peroxisomes.
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PBD061 cells (PEX16-deficient) lack peroxisomal membranes and cannot import PMPs
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PEX16 expression restores peroxisome formation de novo
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PMP import precedes matrix protein import after PEX16 complementation
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Peroxisomes can form without preexisting peroxisomes
PEX3:PEX19:class I PMP dissociates
PEX19:class I PMP binds PEX3
PEX19 binds class I peroxisomal membrane proteins
PEX16:PEX19:Pex3 dissociates