| Summary: | <p>Small heat-shock proteins (sHsps) are a family of molecular chaperones that are a
part of the cellular proteostasis machinery. Many of them, such as human HspB1,
HspB4 and HspB5 are polydisperse–they form a large range of stoichiometries.
Some are also known to co-assemble, forming a large variety of sub-stoichiometries,
with possible implications for their function.</p>
<p>In this work, we first develop theoretical models for studying the co-assembly between
both monodisperse as well as polydisperse proteins using statistical mechanics
and chemical kinetics, respectively. We then briefly apply the statistical-mechanical
model on a system of two co-assembling monodisperse sHsps.</p>
<p>We then use two orthogonal biophysical techniques, native mass spectrometry
(MS) and mass photometry (MP), to study the homo-oligomerisation of the two
most abundant, and highly polydisperse, human sHsps–HspB1 and HspB5. Next,
we use MS and MP to study highly heterogeneous mixtures of these two proteins
on both the level of stoichiometries as well as the sub-stoichiometry level.</p>
<p>We next use the model we have developed and apply it to our mixing data to
obtain both the complete description of these co-assemblies as well as to extract
any energy biases in these mixtures, which we then probe experimentally using
MS, MP and molecular dynamics modelling.</p>
<p>Finally, we study the co-assembly of HspB1, HspB5 and HspB6 between different
vertebrate species and mention that some HspB1 and hspB6 orthologs either
completely lost, or are in the process of losing, their polydispersity. Curiously,
HspB5 orthologs still seem to be polydisperse, which might be due to the functional
role of polydispersity in the eye lens, where HspB5 is highly expressed.</p>
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