Small Heat Shock Protein 27 and Its Role in Human Disease

Bianka Andrea Holguin, University of Texas at El Paso


Small heat shock protein 27 (Hsp27) is a ubiquitously expressed molecular chaperone with roles in many physiological processes. As an ATP-independent molecular chaperone, Hsp27 protects substrates from irreversible aggregation and holds them in a folding competent state for later recycling into the proteome. Hsp27 proteins form dimers that are assembled into large oligomeric complexes. Phosphorylation of Hsp27 dissembles the oligomers into chaperone active dimers. Several missense mutations of Hsp27 are causative for the neurodegenerative disorders Charcot-Marie-Tooth disease 2F and distal Hereditary Motor Neuropathy IIB. Here I show that the oligomerization and chaperoning ability of Hsp27 are altered by the Hsp27 mutations: R127W, R136W, and S135F. I found that the mutations R127W, R136W, and S135F at the dimer interface of Hsp27 cause a gain of function along with increased oligomerization. Additionally, I found that increased monomerization of mutants R136W and R127W correlates with instability and reduced chaperoning activity. The missense mutation T151I, located outside of the dimer interface, had no effect on chaperone activity nor oligomerization patterns. These results highlight the notion that oligomerization and efficient chaperoning activity are highly interconnected processes. Furthermore, I demonstrate that Hsp27 may regulate the release of its substrates through homo-oligomer interactions that occur between adjacent dimers of Hsp27. I found that stronger homo-oligomer interactions correlate with decreased chaperone activity and weaker homo-oligomer interactions correlate with increased chaperoning activity. In addition, I reveal that the mutant S135F has both increased homo-oligomer interactions and increased binding to substrates compared to the wild type Hsp27. My data suggest that the mutant S135F may not efficiently regulate its homo-oligomer interactions. Altered chaperone activity could lead to aberrant binding of client proteins, removing them from important neuronal processes. This ill-timed chaperoning of substrates may be one potential mechanistic mode of disease progression. Together my dissertation work not only advances the knowledge of how Hsp27 may release its substrate but also provides insight into how the missense mutations of Hsp27 associated with Charcot-Marie-Tooth 2F and distal Hereditary Motor Neuropathy IIB affect chaperone activity and substrate release. These are important contributions to our understanding of how Hsp27 functions as a chaperone and its role in human diseases.

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Recommended Citation

Holguin, Bianka Andrea, "Small Heat Shock Protein 27 and Its Role in Human Disease" (2022). ETD Collection for University of Texas, El Paso. AAI10747086.