8SG2

BIVALENT INTERACTIONS OF PIN1 WITH THE C-TERMINAL TAIL OF PKC

Summary for 8SG2

• Entry DOI: 10.2210/pdb8sg2/pdb
• NMR Information: BMRB: 31080
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, Protein kinase C beta type (2 entities in total)
• Functional Keywords: bivalent complex, pin1, protein kinase c, hydrophobic motif, turn motif, isomerase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 21124.20

Authors

Dixit, K.,Yang, Y.,Chen, X.R.,Igumenova, T.I. (deposition date: 2023-04-11, release date: 2024-05-08, Last modification date: 2024-05-15)

Primary citation

Chen, X.R.,Dixit, K.,Yang, Y.,McDermott, M.I.,Imam, H.T.,Bankaitis, V.A.,Igumenova, T.I.
A novel bivalent interaction mode underlies a non-catalytic mechanism for Pin1-mediated protein kinase C regulation.
Elife, 13:-, 2024

PubMed Abstract: Regulated hydrolysis of the phosphoinositide phosphatidylinositol(4,5)-bis-phosphate to diacylglycerol and inositol-1,4,5-P defines a major eukaryotic pathway for translation of extracellular cues to intracellular signaling circuits. Members of the lipid-activated protein kinase C isoenzyme family (PKCs) play central roles in this signaling circuit. One of the regulatory mechanisms employed to downregulate stimulated PKC activity is via a proteasome-dependent degradation pathway that is potentiated by peptidyl-prolyl isomerase Pin1. Here, we show that contrary to prevailing models, Pin1 does not regulate conventional PKC isoforms α and βII via a canonical isomerization of the peptidyl-prolyl bond. Rather, Pin1 acts as a PKC binding partner that controls PKC activity via sequestration of the C-terminal tail of the kinase. The high-resolution structure of full-length Pin1 complexed to the C-terminal tail of PKCβII reveals that a novel bivalent interaction mode underlies the non-catalytic mode of Pin1 action. Specifically, Pin1 adopts a conformation in which it uses the WW and PPIase domains to engage two conserved phosphorylated PKC motifs, the turn motif and hydrophobic motif, respectively. Hydrophobic motif is a non-canonical Pin1-interacting element. The structural information combined with the results of extensive binding studies and experiments in cultured cells suggest that non-catalytic mechanisms represent unappreciated modes of Pin1-mediated regulation of AGC kinases and other key enzymes/substrates.

PubMed: 38687676
DOI: 10.7554/eLife.92884

Experimental method

SOLUTION NMR