Exploring the role of elongation Factor-Like 1 (EFL1) in Shwachman-Diamond syndrome through molecular dynamics

DOI: 10.1080/07391102.2019.1704883

Authors: Pietro Delre (Università degli Studi di Bari “Aldo Moro”; Consiglio Nazionale delle Ricerche) , Domenico Alberga (Cineca) , Abril Gijsbers (Maastricht University) , Nuria Sánchez-Puig (Universidad Nacional Autónoma de México) , Orazio Nicolotti (Università̀ degli Studi di Bari “Aldo Moro”) , Michele Saviano (Consiglio Nazionale delle Ricerche) , Dritan Siliqi (Consiglio Nazionale delle Ricerche) , Giuseppe Felice Mangiatordi (Consiglio Nazionale delle Ricerche)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biomolecular Structure And Dynamics

State: Published (Approved)
Published: December 2019
Diamond Proposal Number(s): 21741

Abstract: Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder whose patients present mutations in two ribosome assembly proteins, the Shwachman-Bodian-Diamond Syndrome protein (SBDS) and the Elongation Factor-Like 1 (EFL1). Due to the lack of knowledge of the molecular mechanisms responsible for SDS pathogenesis, current therapy is nonspecific and focuses only at alleviating the symptoms. Building on the recent observation that EFL1 single-point mutations clinically manifest as SDS-like phenotype, we carried out comparative Molecular Dynamics (MD) simulations on three mutants, T127A, M882K and R1095Q and wild type EFL1. As supported by small angle X-ray scattering experiments, the obtained data improve the static EFL1 model resulting from the Cryo-electron microscopy and clearly show that all the mutants experience a peculiar rotation, around the hinge region, of domain IV with respect to domains I and II leading to a different conformation respect to that of wild type protein. This study supports the notion that EFL1 function is governed by an allosteric mechanism involving the concerted action of GTPase domain (domain I) and the domain IV and can help point towards new approaches to SDS treatment.

Journal Keywords: EFL1; Shwachman-Diamond Syndrome; molecular dynamics simulations; point-mutations; SAXS

Diamond Keywords: Shwachman-Diamond Syndrome (SDS)

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS

Added On: 09/01/2020 10:01

Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)