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Crystal structure of the mu2 subunit of the clathrin-adaptor protein 2 (AP2) bound to HPV16 E7(residues 22-32; S31E and S32E)
Structural highlights
FunctionAP2M1_RAT Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. The AP-2 mu subunit binds to transmembrane cargo proteins; it recognizes the Y-X-X-Phi motifs. The surface region interacting with to the Y-X-X-Phi motif is inaccessible in cytosolic AP-2, but becomes accessible through a conformational change following phosphorylation of AP-2 mu subunit at 'Tyr-156' in membrane-associated AP-2. The membrane-specific phosphorylation event appears to involve assembled clathrin which activates the AP-2 mu kinase AAK1 (By similarity). Plays a role in endocytosis of frizzled family members upon Wnt signaling.[1] [2] [3] [4] Publication Abstract from PubMedHuman papillomaviruses (HPVs) cause abnormal cellular proliferation, leading to malignant or benign lesions, such as cervical cancer and warts. The genome of HPV16, the most prevalent high-risk oncogenic genotype within the Alphapapillomavirus genus, encodes two oncoproteins. One of these proteins, E7, interacts with multiple host proteins and modulates their functions through distinct pathways. The CR2 domain of HPV16 E7 was recently reported to interact with the mu2 subunit of clathrin-adaptor protein 2 (AP2-mu2), an adaptor complex involved in cargo internalization during clathrin-mediated endocytosis. In this study, to provide molecular insights into their intermolecular interactions, we determined the crystal structures of AP2-mu2 in complex with the HPV16 E7-derived peptides. Subsequent biochemical analyses revealed that this interaction is primarily maintained by the Y-x-x-Phi motif and further supported by acidic cluster residues of HPV16 E7. Finally, sequence alignment of the E7 CR2 domains from various HPV genotypes showed that the AP2-mu2-binding motif is largely conserved in Alpha-, Beta-, and Mupapillomaviruses, but not in Nu- and Gammapapillomaviruses. Crystal structures of the mu2 subunit of clathrin-adaptor protein 2 in complex with peptides derived from human papillomavirus 16 E7.,Jung S, Lim D, Choi JS, Shin HC, Kim SJ, Ku B J Microbiol. 2025 Aug;63(8):e2505003. doi: 10.71150/jm.2505003. Epub 2025 Aug 31. PMID:40878558[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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