Exploring the role of elongation Factor-Like 1 (EFL1) in Shwachman-Diamond syndrome through molecular dynamics
Por:
Delre, Pietro, Alberga, Domenico, Gijsbers, Abril, Sanchez-Puig, Nuria, Nicolotti, Orazio, Saviano, Michele, Siliqi, Dritan, Mangiatordi, Giuseppe Felice
Publicada:
21 nov 2020
Ahead of Print:
1 dic 2019
Resumen:
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. Communicated by
Ramaswamy H. Sarma
Filiaciones:
Delre, Pietro:
Dipartimento di Chimica, Università Degli Studi di Bari “Aldo Moro”, Bari, Italy
Consiglio Nazionale Delle Ricerche, Istituto di Cristallografia, Bari, Italy
Alberga, Domenico:
Cineca, Casalecchio di Reno, Italy
Gijsbers, Abril:
The Maastricht Multimodal Molecular Imaging Institute (M4I), Division of Nanoscopy, Maastricht University, Maastricht, Netherlands
Sanchez-Puig, Nuria:
Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, Mexico
Nicolotti, Orazio:
Dipartimento di Farmacia—Scienze Del Farmaco, Università` Degli Studi di Bari “Aldo Moro”, Bari, Italy
Saviano, Michele:
Consiglio Nazionale Delle Ricerche, Istituto di Cristallografia, Bari, Italy
Siliqi, Dritan:
Consiglio Nazionale Delle Ricerche, Istituto di Cristallografia, Bari, Italy
Mangiatordi, Giuseppe Felice:
Consiglio Nazionale Delle Ricerche, Istituto di Cristallografia, Bari, Italy
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