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Review
. 2014 Jul 17;21(7):809-18.
doi: 10.1016/j.chembiol.2014.05.010. Epub 2014 Jun 26.

Genetic, structural, and molecular insights into the function of ras of complex proteins domains

Laura Civiero  1 , Sybille Dihanich  2 , Patrick A Lewis  3 , Elisa Greggio  4
Affiliations
Review

Genetic, structural, and molecular insights into the function of ras of complex proteins domains

Laura Civiero et al. Chem Biol. .

Abstract

Ras of complex proteins (ROC) domains were identified in 2003 as GTP binding modules in large multidomain proteins from Dictyostelium discoideum. Research into the function of these domains exploded with their identification in a number of proteins linked to human disease, including leucine-rich repeat kinase 2 (LRRK2) and death-associated protein kinase 1 (DAPK1) in Parkinson's disease and cancer, respectively. This surge in research has resulted in a growing body of data revealing the role that ROC domains play in regulating protein function and signaling pathways. In this review, recent advances in the structural information available for proteins containing ROC domains, along with insights into enzymatic function and the integration of ROC domains as molecular switches in a cellular and organismal context, are explored.

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Figures

Figure 1
Figure 1
Putative Proteins Containing ROC-COR Domains from T. adherens Proteins were identified using blastp searches with D. discoideum COR domains against T. adherens genome (TAXID: 10228). TRP, tetratricopeptide domain; AAA, ATPase domain; MBT, malignant brain tumor repeats; SH3, SRC homology 3 domain; LRRs, leucine-rich repeats; CARD, caspase recruitment domain; TIR, Toll-interleukin receptor domain.
Figure 2
Figure 2
Phylogenetic Relationships among ROCO Proteins (A) Phylogenetic dendograms (constructed using the unweighted pair-group method of analysis) based on the full-length amino acid sequences of prokaryotes (C. tepidum), archea (M. barkeri), placozoa (T. adherens), slime mold (D. discoideum), plants (A. thaliana), invertebrates (C. elegans and D. melanogaster), and vertebrates (D. rerio and H. sapiens). Of note, the closest homolog of human DAPK1 is plant Tornado1; MFHAS1 proteins are closer to Dyctiostelium ROCO than to LRRKs; and Drosophila LRRK and Caenorabditis LRK-1 are closer to LRRK1 than to LRRK2. (B) Phylogenetic dendograms from the same species using the predicted ROC-COR domains. LRRK1’s closest ROC-COR domain is LRRK2.
Figure 3
Figure 3
Functional Interactions between the ROC Domain and Other Protein Domains Associated with It
Figure 4
Figure 4
Strategies to Target ROC Domain Activity Image of C. tepidum ROCO protein derived from Protein Data Bank reference 3PDU (Gotthardt et al., 2008).
See this image and copyright information in PMC

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