Abstract

The Shwachman-Diamond Syndrome (SDS) is a disorder arising from mutations in thegenes encoding for the Shwachman-Bodian-Diamond Syndrome (SBDS) protein and the GTPaseknown as Elongation Factor Like-1 (EFL1). Together, these proteins remove the anti-associationfactor eIF6 from the surface of the pre-60S ribosomal subunit to promote the formation of matureribosomes. SBDS missense mutations can either destabilize the protein fold or affect surface epitopes.The molecular alterations resulting from the latter remain largely unknown, although some evidencesuggest that binding to EFL1 may be affected. We further explored the effect of these SBDS mutationson the interaction with EFL1, and showed that all tested mutations disrupted the binding to EFL1.Binding was either severely weakened or almost abolished, depending on the assessed mutation.In higher eukaryotes, SBDS is essential for development, and lack of the protein results in earlylethality. The existence of patients whose only source of SBDS consists of that with surface missensemutations highlights the importance of the interaction with EFL1 for their function. Additionally,we studied the interaction mechanism of the proteins in solution and demonstrated that bindingconsists of two independent and cooperative events, with domains 2-3 of SBDS directing the initialinteraction with EFL1, followed by docking of domain 1. In solution, both proteins exhibited largeflexibility and consisted of an ensemble of conformations, as demonstrated by Small Angle X-rayScattering (SAXS) experiments.

Autore Pugliese

• Siliqi Dritan

Tutti gli autori

• A. Gijsbers; D.C. Montagut; A. Méndez-Godoy; D. Altamura; M. Saviano; D. Siliqi; N. Sánchez-Puig

Titolo volume/Rivista

International journal of molecular sciences

Anno di pubblicazione

2018

ISSN

1422-0067

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

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Numero di citazioni Scopus

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Ultimo Aggiornamento Citazioni

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Settori ERC

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Codici ASJC

Non Disponibile