{PDOC50108}
{PS50108; CRIB}
{BEGIN}
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* CRIB domain profile *
***********************

Many putative  downstream effectors of the small GTPases Cdc42 and Rac contain
a GTPase binding domain (GBD), also called p21 binding domain (PBD), which has
been shown  to  specifically  bind  the GTP bound form of Cdc42 or Rac, with a
preference for  Cdc42  [1,2].  The most conserved region of GBD/PBD domains is
the N-terminal  Cdc42/Rac  interactive binding motif (CRIB), which consists of
about 16  amino acids with the consensus sequence I-S-x-P-x(2,4)-F-x-H-x(2)-H-
V-G [3].  Although  the  CRIB  motif is necessary for the binding to Cdc42 and
Rac, it  is  not  sufficient  to give high-affinity binding [4,5]. A less well
conserved inhibitory  switch  (IS)  domain  responsible  for  maintaining  the
proteins in  a basal (autoinhibited) state is located C-terminaly of the CRIB-
motif [6,7,8].

GBD domains  can  adopt  related  but  distinct  folds  depending  on context.
Although GBD  domains  are  largely  unstructured  in  the  free state, the IS
domain forms   an   N-terminal  beta  hairpin  that  immediately  follows  the
conserved CRIB  motif  and  a  central  bundle  of  three alpha helices in the
autoinhibited state.  The interaction between GBD domains and their respective
G proteins  leads  to  the  formation  of  a  high-affinity  complex  in which
unstructured regions  of  both  the  effector  and the G protein become rigid.
CRIB motifs  from various GBD domains interact with Cdc42 in a similar manner,
forming an  intermolecular beta-sheet with strand beta-2 of Cdc42. Outside the
CRIB motif,  the  C-termini  of the various GBD domains are very divergent and
show variation  in  their  mode  of  binding to Cdc42, perhaps determining the
specificity of  the  interaction.  Binding  of  Cdc42 or Rac to the GBD domain
causes a  dramatic  conformational change, refolding part of the IS domain and
unfolding the rest [4,6,7,8,9,10].

Some proteins known to contain a CRIB domain are listed below:

 - Mammalian  activated  Cdc42-associated kinases (ACKs), nonreceptor tyrosine
   kinases implicated in integrin-coupled pathways.
 - Mammalian  p21-activated  kinases  (PAK1 to PAK4), serine/threonine kinases
   that modulate cytoskeletal assembly and activate MAP-kinase pathways.
 - Mammalian  Wiskott-Aldrich  Symdrom  Proteins  (WASPs), non-kinase proteins
   involved in the organization of the actin cytoskeleton.
 - Yeast  STE20  and CLA4, the homologues of mammalian PAKs. STE20 is involved
   in the mating/pheromone MAP kinase cascade.

The profile we developed covers the entire CRIB domain.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: June 2002 / Profile changed.

[ 1] Manser E., Leung T., Salihuddin H., Zhao Z.-S., Lim L.
     "A brain serine/threonine protein kinase activated by Cdc42 and
     Rac1."
     Nature 367:40-46(1994).
     PubMed=8107774; DOI=10.1038/367040a0
[ 2] Symons M., Derry J.M.J., Karlak B., Jiang S., Lemahieu V., Mccormick F.,
     Francke U., Abo A.
     "Wiskott-Aldrich syndrome protein, a novel effector for the GTPase
     CDC42Hs, is implicated in actin polymerization."
     Cell 84:723-734(1996).
     PubMed=8625410
[ 3] Burbelo P.D., Drechsel D., Hall A.
     "A conserved binding motif defines numerous candidate target proteins
     for both Cdc42 and Rac GTPases."
     J. Biol. Chem. 270:29071-29074(1995).
     PubMed=7493928
[ 4] Rudolph M.G., Bayer P., Abo A., Kuhlmann J., Vetter I.R.,
     Wittinghofer A.
     "The Cdc42/Rac interactive binding region motif of the Wiskott Aldrich
     syndrome protein (WASP) is necessary but not sufficient for tight
     binding to Cdc42 and structure formation."
     J. Biol. Chem. 273:18067-18076(1998).
     PubMed=9660763
[ 5] Thompson G., Owen D., Chalk P.A., Lowe P.N.
     "Delineation of the Cdc42/Rac-binding domain of p21-activated
     kinase."
     Biochemistry 37:7885-7891(1998).
     PubMed=9601050; DOI=10.1021/bi980140+
[ 6] Kim A.S., Kakalis L.T., Abdul-Manan N., Liu G.A., Rosen M.K.
     "Autoinhibition and activation mechanisms of the Wiskott-Aldrich
     syndrome protein."
     Nature 404:151-158(2000).
     PubMed=10724160; DOI=10.1038/35004513
[ 7] Lei M., Lu W., Meng W., Parrini M.-C., Eck M.J., Mayer B.J.,
     Harrison S.C.
     "Structure of PAK1 in an autoinhibited conformation reveals a
     multistage activation switch."
     Cell 102:387-397(2000).
     PubMed=10975528
[ 8] Hoffman G.R., Cerione R.A.
     "Flipping the switch: the structural basis for signaling through the
     CRIB motif."
     Cell 102:403-406(2000).
     PubMed=10966102
[ 9] Mott H.R., Owen D., Nietlispach D., Lowe P.N., Manser E., Lim L.,
     Laue E.D.
     "Structure of the small G protein Cdc42 bound to the GTPase-binding
     domain of ACK."
     Nature 399:384-388(1999).
     PubMed=10360579; DOI=10.1038/20732
[10] Morreale A., Venkatesan M., Mott H.R., Owen D., Nietlispach D.,
     Lowe P.N., Laue E.D.
     Nat. Struct. Biol. 7:384-388(2000).

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