CRIB effector disorder: exquisite function from chaos

Abstract

The CRIB (Cdc42/Rac interactive binding) family of small G-protein effectors contain significant regions with intrinsic disorder. The G-protein-binding regions are contained within these intrinsically disordered regions. Most CRIB proteins also contain stretches of basic residues associated with their G-protein-binding regions. The basic region (BR) and G-protein-binding region together allow the CRIB effectors to bind to their cognate G-protein via a dock- and coalesce-binding mechanism. The BRs of these proteins take on multiple roles: steering G-protein binding, interacting with elements of the membrane and regulating intramolecular regulatory interactions. The ability of these regions of the CRIBs to undergo multivalent interactions and mediate charge neutralizations equips them with all the properties required to drive liquid-liquid phase separation and therefore to initiate and drive signalosome formation. It is only recently that the structural plasticity in these proteins is being appreciated as the driving force for these vital cellular processes.

Cdc42/Rac Interactive Binding Containing Effector Proteins in Unicellular Protozoans With Reference to Human Host: Locks of the Rho Signaling

“…This establishes that the CRIB motif prefers GTP-loaded GTPases and exhibits decreased binding activity with GDP form. Apart from GTP bound state, the flanking sequence of the CRIB motif also determines Cdc42/Rac binding specificity ( Pirone et al, 2001 ; Owen and Mott, 2018 ). The typical example of such specificity is an autoinhibitory domain of PAKs located C-terminally to the CRIB/PBD domain ( Lei et al, 2000 ; Kim et al, 2016 ).…”

“…Similarly, the cell-polarity signaling pathway also involves the CRIB effector proteins, triggered only by Cdc42 ( Neudauer et al, 1998 ; Bishop and Hall, 2000 ; Vlahou and Rivero, 2006 ). The effector proteins of Cdc42/Rac are diverse in domain architecture and function, which includes Ser/Thr kinase, cytosolic Tyrosine kinase, actin-associated proteins, adaptor proteins, and miscellaneous ( Owen and Mott, 2018 ). Ser/Thr kinases include PAKs, myotonic dystrophy kinase-related Cdc42 binding kinases (MRCKs) and mixed-lineage kinases (MLKs) family.…”

“…Ser/Thr kinases include PAKs, myotonic dystrophy kinase-related Cdc42 binding kinases (MRCKs) and mixed-lineage kinases (MLKs) family. In Tyrosine kinase, only one family of activated Cdc42-associated Tyrosine kinase (ACK) contain a CRIB motif ( Bishop and Hall, 2000 ; Pirone et al, 2000 ; Owen and Mott, 2018 ). Actin associated proteins include Wiskott Aldrich syndrome protein (WASP), WASP-like verproline-homologous protein (WAVE), IQ motif-containing GTPase-activating proteins (IQGAP) and formin families of proteins ( Bishop and Hall, 2000 ; Owen and Mott, 2018 ).…”

“…In Tyrosine kinase, only one family of activated Cdc42-associated Tyrosine kinase (ACK) contain a CRIB motif ( Bishop and Hall, 2000 ; Pirone et al, 2000 ; Owen and Mott, 2018 ). Actin associated proteins include Wiskott Aldrich syndrome protein (WASP), WASP-like verproline-homologous protein (WAVE), IQ motif-containing GTPase-activating proteins (IQGAP) and formin families of proteins ( Bishop and Hall, 2000 ; Owen and Mott, 2018 ). Partitioning defective (PAR) proteins belong to adaptor proteins of cytoskeleton assembly.…”

“…Partitioning defective (PAR) proteins belong to adaptor proteins of cytoskeleton assembly. Small protein effector of Cdc42 (SPEC) and Cdc42 effector protein (CEP)/Binder of Rho GTPases (Borg) ( Joberty et al, 1999 ; Hirsch et al, 2001 ) family of proteins fall under the miscellaneous group because they have not been designated under any specific classification ( Owen and Mott, 2018 ).…”