Structural Implications of Missense Point Mutations in Shwachman–Bodian–Diamond Syndrome Protein (SBDS): A Combined SAXS/MD Investigation

TL;DR

This study explores how specific mutations in the SBDS protein affect its structure and function, using simulations and experiments to understand their role in disease.

Contribution

The study provides a structural rationale for how specific SBDS mutations disrupt interactions with EFL1 and ribosomes.

Findings

Mutations I167T, R175W, and I212T weaken SBDS-EFL1 interactions.

SAXS data show altered conformational states in R19Q, I167T, and R175W mutants.

MD simulations reveal changes in SBDS interdomain flexibility linked to disease.

Abstract

Shwachman–Diamond syndrome (SDS) is a rare autosomal
recessive
disorder characterized by pleiotropic phenotypes, including pancreatic
insufficiency, skeletal abnormalities, and bone marrow dysfunction.
Notably, patients with SDS exhibit an increased risk of developing
myelodysplastic syndrome and leukemia. In this study, we employed
a combination of comparative molecular dynamics (MD) simulations and
small-angle X-ray scattering (SAXS)-based analysis to investigate
the Shwachman–Bodian–Diamond syndrome protein (SBDS).
Specifically, we explored the molecular basis of the syndrome by examining
the conformational dynamics of a set of missense mutants of SBDS in
comparison to those of the wild-type (WT) protein. Our observations
suggest that different mutations may impact (i) the interaction of
SBDS with the ribosome, (ii) the binding of SBDS to Elongation Factor-Like
1 (EFL1), and (iii) the SBDS rearrangements coupled to EFL1 binding.
Extensive MD simulations, with a total simulation time of 17 μs,
revealed variations in the interdomain flexibility of SBDS, which
are consistent with previously published affinity data and the new
SAXS experimental data presented here. We propose a structural rationale
behind the previously reported weak interaction of mutants I167T,
R175W, and I212T with EFL1. Additionally, SAXS data indicate that
R19Q, I167T, and R175W mutants exhibit altered relative abundances
of SBDS conformational states in solution, further supporting our
computational results. Overall, our integrated computational and experimental
approach provides a comprehensive understanding of how specific mutations
in SBDS alter its structural dynamics and binding interactions. These
insights enhance our broader understanding of SBDS function and its
role in ribosome biogenesis.

Figures