Structural basis of Cullin-RING ligase regulation by the COP9 signalosome

Información del proyecto

EMCOP9CRL

Identificador del acuerdo de subvención: 655801

DOI

10.3030/655801

Proyecto finalizado el 3 Febrero 2018

Fecha de la firma de la CE 27 Marzo 2015

Fecha de inicio 12 Octubre 2015

Fecha de finalización 11 Octubre 2017

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 183 454,80

Aportación de la UE

€ 183 454,80

Coordinado por

INSTITUTE OF CANCER RESEARCH: THE ROYAL CANCER HOSPITAL LBG
United Kingdom

Objetivo

The components of the Cullin-RING Ligase (CRLs) E3 ubiquitin ligase family play key roles in a wide range of cellular processes including stress response, signal transduction, apoptosis and cell cycle progression, and accordingly, defects in their function and/or regulation are prominent in many pathologies including cancer. The modular CRL architecture is centred upon one of seven different cullin scaffold proteins which associate on one side with a RING protein that acts as receptor for an E2 ligase and, on the opposite side, with a substrate receptor (SR) that confers specificity to the complex. The multiplicity of SRs allows the recognition of many different substrates by the same CRL catalytic core. CRL-mediated ubiquitination modulates the substrate´s biological activity and in many cases targets them for proteasomal degradation. The COP9 signalosome (CSN) complex plays a fundamental role in CRL regulation both by forming stable inhibitory complexes with the CRLs where the E2 ligase and substrate binding sites are occluded, and by enzymatically removing Nedd8 (a homologue of ubiquitin) from the cullin scaffold subunit, in a process termed deneddylation, that leads to inactivation of CRLs. CRL regulation by CSN is still an incompletely understood topic mostly because of the lack of high resolution CSN/CRL structures due to the challenge that the crystallization of multi-protein assemblies of such complexity represents. Fortunately, recent technological developments in another structural technique, cryoelectron microscopy, now allow structure determination of relatively small protein complexes (< 500kDa) to near-atomic resolution. Hence, we propose to use this powerful technique to reveal very high-resolution structures of several different CSN/CRL holocomplexes and shed light on the mechanistic aspects of their function.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias naturales › ciencias físicas › óptica › microscopía
• ciencias médicas y de la salud › medicina clínica › oncología
• ciencias médicas y de la salud › medicina básica › patología

Palabras clave

• cryoelectron microscopy
• single particle
• image processing
• ubiquitin-proteasome system
• cop9 signalosome
• cullin-ring ligase

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF)
  

Régimen de financiación

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

Convocatoria de propuestas

H2020-MSCA-IF-2014

Coordinador

INSTITUTE OF CANCER RESEARCH: THE ROYAL CANCER HOSPITAL LBG

• Aportación neta de la UEn: € 183 454,80
• Dirección: OLD BROMPTON ROAD 123 ; SW7 3RP London ; Reino Unido
• Región: London › Inner London — West › Kensington & Chelsea and Hammersmith & Fulham
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 183 454,80