| Function/Role | Molecular Mechanism | Key Domains/Motifs | Binding Partners | Subcellular Localization | Biological Processes |
|---|---|---|---|---|---|
| NatA regulatory subunit / co-translational processing factor | HYPK physically associates with the human NatA complex (NAA10-NAA15), has a strong stabilizing effect on the complex, and inhibits NAA10 catalytic activity. Structural studies indicate HYPK binding to the NAA15 helical scaffold induces conformational rearrangements that can allosterically hinder NAA50 association, helping regulate the composition and activity of ribosome-bound N-terminal acetylation machinery. HYPK is therefore a regulator, not a catalytic enzyme itself. (pqac-00000005, pqac-00000006, pqac-00000016) | C-terminal three-helix bundle UBA domain; central long α-helix; extended/disordered N-terminus; Huntingtin-int_K/HYPK_UBA-compatible architecture from UniProt is consistent with the NatA-bound structural literature. (pqac-00000006, pqac-00000016) | NAA10, NAA15, indirectly antagonizes NAA50 association with NatA; functionally linked to NAC and MAP1/MAP2 assemblies on the ribosome. (pqac-00000006, pqac-00000008) | Ribosome-associated; polysome-associated; positioned near the ribosomal polypeptide tunnel exit together with NatA and NAC during nascent-chain processing. (pqac-00000006, pqac-00000007) | Co-translational N-terminal acetylation; coordination of N-terminal methionine excision and N-terminal acetylation; early protein biogenesis and proteostasis. (pqac-00000001, pqac-00000006, pqac-00000008) |
| Organizer of ribosome-proximal multi-enzyme assemblies | Recent cryo-EM work places NatA in a distal ribosomal site compatible with co-occupancy by MAP2 or by NAC-MAP1. HYPK-associated structural rearrangements in NAA15 resemble part of the plasticity required for ribosome engagement, supporting a model in which HYPK helps tune assembly states of the co-translational processing apparatus rather than acting as a substrate-binding enzyme. (pqac-00000006) | Interface-forming helical architecture; flexible/disordered N-terminus likely supports dynamic assembly; C-terminal UBA domain homologous in part to NACα C-terminus per recent discussion. (pqac-00000006) | NatA complex, NAC, MAP1/MAP2-linked ribosome processing environment. (pqac-00000006) | 80S ribosome surface at/near the polypeptide exit tunnel. (pqac-00000001, pqac-00000006) | Dynamic assembly of ribosome-associated factors; coordination of sequential processing of nascent polypeptides. (pqac-00000001, pqac-00000006) |
| Selective autophagy receptor for polyneddylated cargo | HYPK acts as a scaffold that links polyneddylated aggregates to the autophagy machinery. It binds NEDD8 through its C-terminal UBA domain and binds LC3/GABARAP proteins through an N-terminal atypical LC3-interacting region, thereby promoting autophagic sequestration and degradation of neddylated protein aggregates. This defines HYPK as an autophagy receptor in NEDD8-dependent aggrephagy. (pqac-00000004, pqac-00000018, pqac-00000019) | C-terminal UBA domain; N-terminal atypical tyrosine-type LIR motif Y49AEE52. (pqac-00000018, pqac-00000019) | NEDD8; LC3A; LC3B; GABARAP; GABARAPL1; GABARAPL2. (pqac-00000018, pqac-00000019) | Cytoplasmic puncta/granules; colocalizes with NEDD8 granules and LC3-positive autophagic structures during proteotoxic stress. (pqac-00000013, pqac-00000018) | Selective autophagy; aggrephagy; proteotoxic stress response; clearance of insoluble protein aggregates. (pqac-00000004, pqac-00000013, pqac-00000018) |
| NEDD8-binding cargo adaptor | HYPK noncovalently binds monomeric NEDD8 and polyneddylated chains. Mutational analysis identified conserved UBA residues D94, E101, L113, and G118 as important for efficient NEDD8 binding; modeling suggests E101 and G118 are exposed for direct interaction whereas D94 and L113 help stabilize the UBA fold. (pqac-00000019) | UBA domain; critical residues D94, E101, L113, G118. (pqac-00000019) | NEDD8; likely recognizes polyneddylated aggregate cargo including mutant HTT exon 1. (pqac-00000012, pqac-00000019) | Cytoplasm, especially stress-induced aggregate-containing regions. (pqac-00000013, pqac-00000019) | Recognition of neddylated aggregates as autophagic cargo; noncanonical NEDD8-mediated protein quality control. (pqac-00000004, pqac-00000019) |
| LC3/GABARAP-binding autophagy scaffold | HYPK contains a noncanonical Y-type LIR in its N-terminal region. Biochemical and cell-based assays show full-length HYPK and its N-terminal fragment bind LC3B, whereas mutation of the Y49/E51/E52 region disrupts this interaction, demonstrating a direct mechanism for autophagosome recruitment. (pqac-00000018) | Atypical LIR motif Y49AEE52 in N-terminal region. (pqac-00000018) | LC3B and other ATG8-family proteins. (pqac-00000018) | Cytoplasmic autophagic membranes/puncta. (pqac-00000018) | Autophagosome formation and maturation; selective autophagy receptor function. (pqac-00000018) |
| Positive modulator of basal and stress-induced autophagy | HYPK depletion lowers LC3B-II levels and LC3 puncta, whereas overexpression increases autophagosomes and supports ongoing autophagic flux and autolysosome formation. Thus HYPK is not only a cargo receptor but also a positive regulator of autophagy efficiency in several human cell systems. (pqac-00000018) | UBA-LIR dual-module scaffold; self-oligomerization-promoting regions contribute to puncta formation. (pqac-00000018, pqac-00000019) | LC3 family proteins; NEDD8-modified cargo; autophagy machinery downstream of cargo recognition. (pqac-00000018, pqac-00000019) | Cytoplasm; autophagosome/autolysosome pathway. (pqac-00000018) | Basal autophagy; stress-induced autophagy; autophagic flux maintenance. (pqac-00000013, pqac-00000018) |
| Proteostasis factor linked to mutant huntingtin aggregate clearance | In cell models, NEDD8 and HYPK promote clearance of mutant HTT exon 1 aggregates by autophagy. HYPK therefore connects its original huntingtin-interacting identity with a mechanistically defined role in aggregate disposal, especially for proteotoxic, aggregation-prone substrates. (pqac-00000004, pqac-00000012, pqac-00000017) | Huntingtin-interacting protein architecture with UBA and LIR modules enabling cargo recognition and autophagy coupling. (pqac-00000017, pqac-00000019) | Mutant HTT exon 1 aggregates; NEDD8; LC3. (pqac-00000012, pqac-00000018) | Cytoplasmic aggregate foci in neuronal and other cultured cells under proteotoxic stress. (pqac-00000012, pqac-00000018) | Aggregate clearance, cytoprotection during proteotoxic stress, Huntington disease-relevant protein quality control. (pqac-00000004, pqac-00000012, pqac-00000017) |
| Context within NatA biology and human disease-related proteostasis | NatA modifies up to ~40-50% of mammalian proteins, primarily iMet-processed N-termini beginning with Ser/Ala/Gly/Thr/Val/Cys; HYPK does not define substrate sequence specificity itself but regulates the major NatA complex that does. Disturbance of NatA biology is linked to developmental disease, underscoring the importance of HYPK as a regulatory component of this pathway. (pqac-00000008, pqac-00000014) | NatA-associated regulatory architecture rather than catalytic GNAT fold. (pqac-00000005, pqac-00000008) | NAA10, NAA15, functionally NAA50-associated NatE states. (pqac-00000008, pqac-00000014) | Ribosome-associated cytosol. (pqac-00000008) | N-terminal acetylome regulation, protein stability control, developmental proteostasis. (pqac-00000008, pqac-00000014) |


*Table: This table summarizes the best-supported molecular functions, domains, interactions, localization, and biological roles of human HYPK from the collected literature. It highlights the protein’s dual roles in NatA-mediated co-translational protein processing and NEDD8-dependent selective autophagy.*