Zizimin1, a novel Cdc42 activator, reveals a new GEF domain for Rho proteins

Meller, Nahum; Irani-Tehrani, Mohammad; Kiosses, William B.; Pozo, Miguel Á. del; Schwartz, Martin A.

doi:10.1038/ncb835

Cited by 159 publications

(205 citation statements)

References 29 publications

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“…Oligomerizes-Sequence analysis of zizimin1 indicated potential coiled coil structures in the last 100 amino acids (9). These structures are often implicated in oligomerization, which prompted us to test whether zizimin1 exists as higher order complexes.…”

Section: Zizimin1mentioning

confidence: 99%

“…HA-tagged zizimin1 constructs were cloned in the pEF4-Myc-His-C vector (Invitrogen) as described (9).…”

Section: Dna Constructsmentioning

confidence: 99%

“…This family includes 11 mammalian genes, which, based on sequence homology, can be divided into a subfamily related to CDM proteins and a subfamily related to zizimin1. The two groups share two conserved domains that we named CZH1 and CZH2 for CDM-zizimin homology 1 and 2, respectively (9). We propose here to name collectively the superfamily CZH proteins.…”

mentioning

confidence: 99%

“…This intermediate is then dissociated by binding of GTP (7). GEFs can therefore be distinguished from other GTPase-interacting proteins by their ability to bind preferentially to the nucleotide-depleted (ND) state compared with GTP-or GDP-bound states (8,9). The classical GEFs for Rho GTPases share a common motif, designated the Dbl homology (DH) domain, that mediates nucleotide exchange (10).…”

mentioning

confidence: 99%

“…Another family of mammalian Rho-GEFs was recently discovered that includes CDM (Ced-5, DOCK180, Myoblast city) proteins that activate Rac, and zizimin1 that activates Cdc42 (9,(12)(13)(14). This family includes 11 mammalian genes, which, based on sequence homology, can be divided into a subfamily related to CDM proteins and a subfamily related to zizimin1.…”

mentioning

confidence: 99%

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The Novel Cdc42 Guanine Nucleotide Exchange Factor, Zizimin1, Dimerizes via the Cdc42-binding CZH2 Domain

Meller

Irani-Tehrani

Ratnikov

et al. 2004

Journal of Biological Chemistry

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Rho family small GTPases are critical regulators of multiple cellular processes and activities. Dbl homology domain-containing proteins are the classical guanine nucleotide exchange factors (GEFs) responsible for activation of Rho proteins. Recently another group of mammalian Rho-GEFs was discovered that includes CDM (Ced-5, DOCK180, Myoblast city) proteins that activate Rac and zizimin1 that activates Cdc42 via a nonconventional GEF module that we named the CZH2 domain. We report here that zizimin1 dimerizes via the CZH2 domain and that dimers are the only form detected. Dimerization was mapped to a ϳ200-amino acid region that overlaps but is distinct from the Cdc42-binding sequences. Rotary shadowing electron microscopy revealed zizimin1 to be a symmetric, V-shaped molecule. Experiments with DOCK180 and homology analysis suggest that dimerization may be a general feature of CZH proteins. Deletion and mutation analysis indicated existence of individual Cdc42-binding sites in the zizimin1 monomers. Kinetic measurements demonstrated increased binding affinity of Cdc42 to zizimin1 at higher Cdc42 concentration, suggesting positive cooperativity. These features are likely to be critical for Cdc42 activation.

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Section: Zizimin1mentioning

confidence: 99%

“…HA-tagged zizimin1 constructs were cloned in the pEF4-Myc-His-C vector (Invitrogen) as described (9).…”

Section: Dna Constructsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Novel Cdc42 Guanine Nucleotide Exchange Factor, Zizimin1, Dimerizes via the Cdc42-binding CZH2 Domain

Meller

Irani-Tehrani

Ratnikov

et al. 2004

Journal of Biological Chemistry

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Structural biology of DOCK‐family guanine nucleotide exchange factors

2022

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Edited by Jacqueline Cherfils DOCK proteins are a family of multi-domain guanine nucleotide exchange factors (GEFs) that activate the RHO GTPases CDC42 and RAC1, thereby regulating several RHO GTPase-dependent cellular processes. DOCK proteins are characterized by the catalytic DHR2 domain (DOCK DHR2 ), and a phosphatidylinositol(3,4,5)P 3 -binding DHR1 domain (DOCK DHR1 ) that targets DOCK proteins to plasma membranes. DOCK-family GEFs are divided into four subfamilies (A to D) differing in their specificities for CDC42 and RAC1, and the composition of accessory signalling domains. Additionally, the DOCK-A and DOCK-B subfamilies are constitutively associated with ELMO proteins that auto-inhibit DOCK GEF activity. We review structural studies that have provided mechanistic insights into DOCK-protein functions. These studies revealed how a conserved nucleotide sensor in DOCK DHR2 catalyses nucleotide exchange, the basis for how different DOCK proteins activate specifically CDC42 and RAC1, and sometimes both, and how upstream regulators relieve the ELMO-mediated auto-inhibition. We conclude by presenting a model for full-length DOCK9 of the DOCK-D subfamily. The involvement of DOCK GEFs in a range of diseases highlights the importance of gaining structural insights into these proteins to better understand and specifically target them.

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