Database Accession: DI1000316
Name: Autoinhibitory region bound to p21-activated kinase 4 (PAK4) kinase domain
PDB ID: 4l67
Experimental method: X-ray (2.80 Å)
Source organism: Homo sapiens
Proof of disorder:
Primary publication of the structure:
Wang W, Lim L, Baskaran Y, Manser E, Song J
NMR binding and crystal structure reveal that intrinsically-unstructured regulatory domain auto-inhibits PAK4 by a mechanism different for that of PAK1.
(2013) Biochem. Biophys. Res. Commun. :
PMID: 23876315
Abstract:
Six human PAK members are classified into groups I (PAKs 1-3) and II (PAK4-6). Previously, only group I PAKs were thought to be auto-inhibited but very recently PAK4, the prototype of group II PAKs, has also been shown to be auto-inhibited by its N-terminal regulatory domain. However, the complete auto-inhibitory domain (AID) sequence remains undefined and the mechanism underlying its auto-inhibition is largely elusive. Here, the N-terminal regulatory domain of PAK4 sufficient for auto-inhibiting and binding Cdc42/Rac was characterized to be intrinsically unstructured, but nevertheless we identified the entire AID sequence by NMR. Strikingly, an AID peptide was derived by deleting the binding-unnecessary residues, which has a Kd of 320nM to the PAK4 catalytic domain. Consequently, the PAK4 crystal structure complexed with the entire AID has been determined, which reveals that the complete kinase cleft is occupied by 20 AID residues composed of an N-terminal α-helix and a previously-identified pseudosubstrate motif, thus achieving auto-inhibition. Our study reveals that PAK4 is auto-inhibited by a novel mechanism which is completely different from that for PAK1, thus bearing critical implications for design of inhibitors specific for group II PAKs.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
protein serine/threonine kinase activity Catalysis of the reactions: ATP + protein serine = ADP + protein serine phosphate, and ATP + protein threonine = ADP + protein threonine phosphate.
Rac GTPase binding Interacting selectively and non-covalently with Rac protein, any member of the Rac subfamily of the Ras superfamily of monomeric GTPases.
cadherin binding involved in cell-cell adhesion Any cadherin binding that occurs as part of the process of cell-cell adhesion.
Biological process:
Rho protein signal transduction A series of molecular signals within the cell that are mediated by a member of the Rho family of proteins switching to a GTP-bound active state.
regulation of mitotic cell cycle Any process that modulates the rate or extent of progress through the mitotic cell cycle.
cell proliferation The multiplication or reproduction of cells, resulting in the expansion of a cell population.
signal transduction by protein phosphorylation A process in which the transfer of one or more phosphate groups to a substrate transmits a signal to the phosphorylated substrate.
actin cytoskeleton organization A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of cytoskeletal structures comprising actin filaments and their associated proteins.
stress-activated protein kinase signaling cascade A series of molecular signals in which a stress-activated protein kinase (SAPK) cascade relays one or more of the signals.
activation of protein kinase activity Any process that initiates the activity of an inactive protein kinase.
regulation of apoptotic process Any process that modulates the occurrence or rate of cell death by apoptotic process.
regulation of MAPK cascade Any process that modulates the frequency, rate or extent of signal transduction mediated by the MAP kinase (MAPK) cascade.
cellular response to organic cyclic compound Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an organic cyclic compound stimulus.
cell-cell adhesion The attachment of one cell to another cell via adhesion molecules.
Cellular component:
cell-cell adherens junction An adherens junction which connects a cell to another cell.
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: B, A
Notes: No modifications of the original PDB file.
Name: Serine/threonine-protein kinase PAK 4
Source organism: Homo sapiens
Length: 25 residues
Sequence:Sequence according to PDB SEQRESPRQWQSLIEESARRPKPLVDPACIT
UniProtKB AC: O96013 (positions: 36-60) Coverage: 4.2%
UniRef90 AC: UniRef90_O96013 (positions: 36-60)
Name: Serine/threonine-protein kinase PAK 4
Source organism: Homo sapiens
Length: 292 residues
Sequence:Sequence according to PDB SEQRESSHEQFRAALQLVVDPGDPRSYLDNFIKIGEGSTGIVCIATVRSSGKLVAVKKMDLRKQQRRELLFNEVVIMRDYQHENVVEMYNSYLVGDELWVVMEFLEGGALTDIVTHTRMNEEQIAAVCLAVLQALSVLHAQGVIHRDIKSDSILLTHDGRVKLSDFGFCAQVSKEVPRRKSLVGTPYWMAPELISRLPYGPEVDIWSLGIMVIEMVDGEPPYFNEPPLKAMKMIRDNLPPRLKNLHKVSPSLKGFLDRLLVRDPAQRATAAELLKHPFLAKAGPPASIVPLMRQNRTR
UniProtKB AC: O96013 (positions: 300-591) Coverage: 49.4%
UniRef90 AC: UniRef90_O96013 (positions: 300-591)
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Chain B:
The interacting region of PAK4 has been shown to be intrinsically disordered in homologous proteins (PMID: 9660763 and PMID: 15821030). The 65-123 region described in IDEAL entry IID50053 covers 60% of the binding sequence in a homologous protein.
Chain A:
The protein kinase domain involved in the interaction is known to adopt a stable structure in isolation (see Pfam domain PF00069). A solved monomeric structure of the domain is represented by PDB ID 1i09.
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). The structure can be rotated by left click and hold anywhere on the structure. Representation options can be edited by right clicking on the structure window.
