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

Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder whose patients presentmutations 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 mechanismsresponsible for SDS pathogenesis, current therapy is nonspecific and focuses only at alleviatingthe symptoms. Building on the recent observation that EFL1 single-point mutations clinically manifestas SDS-like phenotype, we carried out comparative Molecular Dynamics (MD) simulations on threemutants, T127A, M882K and R1095Q and wild type EFL1. As supported by small angle X-ray scatteringexperiments, the obtained data improve the static EFL1 model resulting from the Cryo-electronmicroscopy and clearly show that all the mutants experience a peculiar rotation, around the hingeregion, of domain IV with respect to domains I and II leading to a different conformation respect tothat of wild type protein. This study supports the notion that EFL1 function is governed by an allostericmechanism involving the concerted action of GTPase domain (domain I) and the domain IV andcan help point towards new approaches to SDS treatment.

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