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In cellulo Crystal Structure of PAK4 in complex with Inka
Structural highlights
FunctionPAK4_HUMAN Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, growth, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN.[1] [2] [3] [4] [5] [6] [7] INKA1_HUMAN Inhibitor of the serine/threonine-protein kinase PAK4 (PubMed:26607847). Acts by binding PAK4 in a substrate-like manner, inhibiting the protein kinase activity (PubMed:26607847).[8] Publication Abstract from PubMedPAK4 is a metazoan-specific kinase acting downstream of Cdc42. Here we describe the structure of human PAK4 in complex with Inka1, a potent endogenous kinase inhibitor. Using single mammalian cells containing crystals 50 mum in length, we have determined the in cellulo crystal structure at 2.95 A resolution, which reveals the details of how the PAK4 catalytic domain binds cellular ATP and the Inka1 inhibitor. The crystal lattice consists only of PAK4-PAK4 contacts, which form a hexagonal array with channels of 80 A in diameter that run the length of the crystal. The crystal accommodates a variety of other proteins when fused to the kinase inhibitor. Inka1-GFP was used to monitor the process crystal formation in living cells. Similar derivatives of Inka1 will allow us to study the effects of PAK4 inhibition in cells and model organisms, to allow better validation of therapeutic agents targeting PAK4. An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1.,Baskaran Y, Ang KC, Anekal PV, Chan WL, Grimes JM, Manser E, Robinson RC Nat Commun. 2015 Nov 26;6:8681. doi: 10.1038/ncomms9681. PMID:26607847[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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