{"doi":"10.1074/jbc.m115.676221","title":"Zeta Inhibitory Peptide Disrupts Electrostatic Interactions That Maintain Atypical Protein Kinase C in Its Active Conformation on the Scaffold p62","abstract":"Atypical protein kinase C (aPKC) enzymes signal on protein scaffolds, yet how they are maintained in an active conformation on scaffolds is unclear. A myristoylated peptide based on the autoinhibitory pseudosubstrate fragment of the atypical PKCζ, zeta inhibitory peptide (ZIP), has been extensively used to inhibit aPKC activity; however, we have previously shown that ZIP does not inhibit the catalytic activity of aPKC isozymes in cells (Wu-Zhang, A. X., Schramm, C. L., Nabavi, S., Malinow, R., and Newton, A. C. (2012) J. Biol. Chem. 287, 12879-12885). Here we sought to identify a bona fide target of ZIP and, in so doing, unveiled a novel mechanism by which aPKCs are maintained in an active conformation on a protein scaffold. Specifically, we used protein-protein interaction network analysis, structural modeling, and protein-protein docking to predict that ZIP binds an acidic surface on the Phox and Bem1 (PB1) domain of p62, an interaction validated by peptide array analysis. Using a genetically encoded reporter for PKC activity fused to the p62 scaffold, we show that ZIP inhibits the activity of wild-type aPKC, but not a construct lacking the pseudosubstrate. These data support a model in which the pseudosubstrate of aPKCs is tethered to the acidic surface on p62, locking aPKC in an open, signaling-competent conformation. ZIP competes for binding to the acidic surface, resulting in displacement of the pseudosubstrate of aPKC and re-engagement in the substrate-binding cavity. This study not only identifies a cellular target for ZIP, but also unveils a novel mechanism by which scaffolded aPKC is maintained in an active conformation.","journal":"Journal of Biological Chemistry","year":2015,"id":9519,"datarank":0.5375278407684165,"base_score":3.58351893845611,"endowment":3.58351893845611,"self_citation_contribution":0.5375278407684165,"citation_network_contribution":0.0,"self_endowment_contribution":0.5375278407684165,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0477,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2015-09-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":150,"name":"Lei Xie","orcid":"0000-0001-9051-2111","position":1,"is_corresponding":false},{"id":79812,"name":"Kim Dore","orcid":null,"position":2,"is_corresponding":false},{"id":153,"name":"Li Xie","orcid":"0000-0003-3658-2535","position":3,"is_corresponding":false},{"id":79813,"name":"Jason C. Del Rio","orcid":"0000-0001-8540-2065","position":4,"is_corresponding":false},{"id":79814,"name":"Charles C. King","orcid":null,"position":5,"is_corresponding":false},{"id":79815,"name":"Guillermo Martinez-Ariza","orcid":null,"position":6,"is_corresponding":false},{"id":79816,"name":"Christopher Hulme","orcid":null,"position":7,"is_corresponding":false},{"id":79817,"name":"Roberto Malinow","orcid":"0000-0002-8862-2562","position":8,"is_corresponding":false},{"id":125,"name":"Philip  E. Bourne","orcid":"0000-0002-7618-7292","position":9,"is_corresponding":false},{"id":1614,"name":"Alexandra C. Newton","orcid":"0000-0002-2906-3705","position":10,"is_corresponding":false},{"id":79818,"name":"Kim Doré","orcid":"0000-0001-6263-367X","position":11,"is_corresponding":false},{"id":79819,"name":"Guillermo Martinez‐Ariza","orcid":"0000-0003-2002-3958","position":12,"is_corresponding":false},{"id":79811,"name":"Li-Chun Lisa Tsai","orcid":null,"position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}