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Elucidating the role of disulfide bond on amyloid formation and fibril
reversibility of somatostatin-14: relevance to its storage and secretion
#MMPMID24782311
Anoop A
; Ranganathan S
; Das Dhaked B
; Jha NN
; Pratihar S
; Ghosh S
; Sahay S
; Kumar S
; Das S
; Kombrabail M
; Agarwal K
; Jacob RS
; Singru P
; Bhaumik P
; Padinhateeri R
; Kumar A
; Maji SK
J Biol Chem
2014[Jun]; 289
(24
): 16884-903
PMID24782311
show ga
The storage of protein/peptide hormones within subcellular compartments and
subsequent release are crucial for their native function, and hence these
processes are intricately regulated in mammalian systems. Several peptide
hormones were recently suggested to be stored as amyloids within endocrine
secretory granules. This leads to an apparent paradox where storage requires
formation of aggregates, and their function requires a supply of non-aggregated
peptides on demand. The precise mechanism behind amyloid formation by these
hormones and their subsequent release remain an open question. To address this,
we examined aggregation and fibril reversibility of a cyclic peptide hormone
somatostatin (SST)-14 using various techniques. After proving that SST gets
stored as amyloid in vivo, we investigated the role of native structure in
modulating its conformational dynamics and self-association by disrupting the
disulfide bridge (Cys(3)-Cys(14)) in SST. Using two-dimensional NMR, we resolved
the initial structure of somatostatin-14 leading to aggregation and further
probed its conformational dynamics in silico. The perturbation in native
structure (S-S cleavage) led to a significant increase in conformational
flexibility and resulted in rapid amyloid formation. The fibrils formed by
disulfide-reduced noncyclic SST possess greater resistance to denaturing
conditions with decreased monomer releasing potency. MD simulations reveal marked
differences in the intermolecular interactions in SST and noncyclic SST providing
plausible explanation for differential aggregation and fibril reversibility
observed experimentally in these structural variants. Our findings thus emphasize
that subtle changes in the native structure of peptide hormone(s) could alter its
conformational dynamics and amyloid formation, which might have significant
implications on their reversible storage and secretion.
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