A functional requirement for PAK1 binding to the KH(2) domain of the fragile X protein-related FXR1.
Loss of fragile X mental retardation protein FMR1 is the most common genetic cause of mental deficiency in man. We find that both FMR1 and the related FXR1 serve as direct binding partners for the Cdc42 effector PAK1. This involves an 11 residue segment in the PAK1 autoinhibitory domain that is exposed upon kinase activation and binds the FXR1 KH2 domain. Active PAK1 can phosphorylate FXR1 at Ser420; antibodies to this site show increased phosphorylation when fragile X proteins are recruited to stress granules. During zebrafish muscle development, FXR1 Ser420 phosphorylation is needed for protein function. The familial FMR1(I304N) mutation is biologically inactive, and FXR1(I304N) fails to bind PAK1. A different PAK1 binding-deficient mutant, FXR1(Q348K/E352A), fails to rescue loss of Zf-FXR1 unless combined with a gain-of-function S420D phosphomimetic. This is the first documented protein partner for the KH(2) domain of FMR1 or FXR1, and it has several implications for signaling by fragile X proteins.
Say
Evonne
E
sGSK Group at IMCB, Neuroscience Research Partnership, Singapore.
Tay
Hwee-Goon
HG
Zhao
Zhuo-shen
ZS
Baskaran
Yohendran
Y
Li
Rong
R
Lim
Louis
L
Manser
Ed
E
D000595:Amino Acid Sequence; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000737:chemistry; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
D051860:Fragile X Messenger Ribonucleoprotein 1; D005982:Glutathione Transferase; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D011993:Recombinant Fusion Proteins; D054462:p21-Activated Kinases; C515903:PAK1 protein, human