REVIEWS & COMMENTS

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STRUCTURAL BIOLOGY OF DOCK-FAMILY GUANINE NUCLEOTIDE EXCHANGE FACTORS

FEBS Letter; October 21, 2022

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 (DOCKDHR2), and a phosphatidylinositol(3,4,5)P3-binding DHR1 domain (DOCKDHR1) that targets DOCK proteins to plasma membranes. DOCK-family GEFs are divided into four sub-families (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 function. These studies revealed how a conserved nucleotide sensor in DOCKDHR2 catalyses nucleotide exchange, the basis for how different DOCK proteins activate specifically CDC42 and RAC1, and sometimes both, and how up-stream 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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CEMIP (HYBID, KIAA1199): STRUCTURE, FUNCTION AND EXPRESSION IN HEALTH AND DISEASE

FEBS Journal; August 23, 2022

CEMIP (Cell migration-inducing protein), also known as KIAA1199 or HYBID, is a protein involved in the depolymerization of hyaluronic acid (HA), a major glycosaminoglycan component of the extracellular matrix. CEMIP was originally described in patients affected by non-syndromic hearing loss and has subsequently been shown to play a key role in tumor initiation and progression, as well as arthritis, atherosclerosis and idiopathic pulmonary fibrosis. Despite the vast literature associating CEMIP with these diseases, its biology remains elusive. The present review article summarizes all the major scientific evidence regarding its structure, function, role and expression, and attempts to cast light on a protein that modulates EMT, fibrosis and tissue inflammation, an unmet key aspect in several inflammatory disease conditions.

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DECIPHERING THE MODES OF HUMAN SEPARASE INHIBITION BY SECURIN AND CDK1-CCNB1

Molecular & Cellular Oncology; September 24th, 2021

Accurate chromosome segregation depends on tight regulation of the protease separase, which cleaves the ring-shaped cohesin complex that entraps the two sister chromatids. We recently reported structures of human separase bound to its inhibitors securin or the cyclin-dependent kinase 1 (CDK1)-cyclin B1 (CCNB1)-cyclin-dependent kinases regulatory subunit 1 (CKS1) complex and discovered an array of molecular mechanisms that block cohesin-cleavage.

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THE POTENTIAL OF CRYO-ELECTRON MICROSCOPY FOR STRUCTURE-BASED DRUG DESIGN

Essays in Biochemistry; November 8th, 2017

Structure-based drug design plays a central role in therapeutic development. Until recently, protein crystallography and NMR have dominated experimental approaches to obtain structural information of biological molecules. However, in recent years rapid technical developments in single particle cryo-electron microscopy (cryo-EM) have enabled the determination to near-atomic resolution of macromolecules ranging from large multi-subunit molecular machines to proteins as small as 64 kDa. These advances have revolutionized structural biology by hugely expanding both the range of macromolecules whose structures can be determined, and by providing a description of macromolecular dynamics. Cryo-EM is now poised to similarly transform the discipline of structure-based drug discovery. This article reviews the potential of cryo-EM for drug discovery with reference to protein ligand complex structures determined using this technique.