Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4)

Integrin adhesion receptors provide links between extracellular ligands and cytoplasmic signaling. Multiple kinases have been found to directly engage with integrin β tails, but the molecular basis for these interactions remain unknown. Here, we assess the interaction between the kinase domain of p2...

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Vydáno v:Communications biology Ročník 5; číslo 1; s. 1257 - 11
Hlavní autoři: Ha, Byung Hak, Yigit, Sezin, Natarajan, Nalini, Morse, Elizabeth M., Calderwood, David A., Boggon, Titus J.
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 17.11.2022
Nature Publishing Group
Nature Portfolio
Témata:
631/45/275
631/535/1266
82/1
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96/95
Amino Acid Sequence
Binding sites
Biology
Biomedical and Life Sciences
Integrins - genetics
Integrins - metabolism
Kinases
Life Sciences
p21-activated kinase
p21-Activated Kinases - genetics
p21-Activated Kinases - metabolism
Platelet Glycoprotein GPIb-IX Complex
Site-directed mutagenesis
ISSN:2399-3642, 2399-3642
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Shrnutí:Integrin adhesion receptors provide links between extracellular ligands and cytoplasmic signaling. Multiple kinases have been found to directly engage with integrin β tails, but the molecular basis for these interactions remain unknown. Here, we assess the interaction between the kinase domain of p21-activated kinase 4 (PAK4) and the cytoplasmic tail of integrin β5. We determine three crystal structures of PAK4-β5 integrin complexes and identify the PAK-binding site. This is a region in the membrane-proximal half of the β5 tail and confirmed by site-directed mutagenesis. The β5 tail engages the kinase substrate-binding groove and positions the non-phosphorylatable integrin residue Glu767 at the phosphoacceptor site. Consistent with this, integrin β5 is poorly phosphorylated by PAK4, and in keeping with its ability to occlude the substrate-binding site, weakly inhibits kinase activity. These findings demonstrate the molecular basis for β5 integrin-PAK4 interactions but suggest modifications in understanding the potential cellular role of this interaction. Crystal structures of integrin β5 tails with PAK4 reveal a unique interaction in which integrin β5 is not phosphorylated by PAK4 but rather inhibits PAK4 activity.
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ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-022-04157-3