HSPBs: Small proteins with big implications in human disease

ArticleinThe international journal of biochemistry & cell biology 44(10):1706-10 · June 2012with22 Reads
Impact Factor: 4.05 · DOI: 10.1016/j.biocel.2012.06.005 · Source: PubMed

Although initially somewhat ignored, recent studies have now clearly established that the diverse members of the human family of small HSPs (HSPB1-HSPB10) play crucial roles in a wide range of cell types to maintain the integrity and function of tissues, in particular that of nervous and muscular tissue. The 10 human HSPBs clearly have overlapping and non-overlapping functional characteristics. Their ability to self- and hetero-oligomerise provides the cells with a large array of potentially different, specific functions. Single HSPB members can have a multitude of functions (moonlighting) and act on different "clients", thus affecting a wide range of different processes or structures that can ultimately affect the rate of aging of tissues and entire organisms. This is underscored by the findings that some inherited diseases involve mutations in several HSPB members that cause premature (mostly muscle and neuronal) tissue degeneration. Inversely, cancer cell resistance to different anticancer therapies is associated with elevated expression of several HSPBs. Still, many unanswered questions exist about the precise functioning of HSPBs, their collaboration with other HSPB members as well as their functions within the entire cellular chaperone network. Also, better insight in the regulation of expression of the various members and how their function is modulated post-translationally is needed. Such may be crucially important to develop means to intervene with their function for therapeutic purposes, which would require functional down-regulation in cancer but up-regulation in, for instance, cardiac or degenerative neuro/neuromuscular diseases. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.

    • "Despite their generally recognized relevance to cellular survival, cellular migration and to tissue remodelling and repair [36, 37], surprisingly little is known about the role of small HSPs in MS. With the exception of HSPB5, only limited data are available on their expression profiles during the development of MS lesions, even though such profiles may hold important clues to molecular factors involved in the disease process. "
    Full-text · Article · Dec 2015
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    • "In the cell, sHsps cooperate with members of the Hsp70/40 system for re-activation of their substrate proteins (Ehrnsperger et al., 1997; Haslbeck et al., 2005b; Lee et al., 1997; Mogk et al., 2003; Veinger et al., 1998). Due to this cyto-protective role, mutations in sHsps are implicated in a variety of diseases, such as cataract, neuropathies , and cancer (Kampinga and Garrido, 2012; Sun and MacRae, 2005). The most prominent sHsp, a-crystallin, is important for eye lens transparency and is also eponymous for the homology domain common to all sHsps (Horwitz, 2003). "
    [Show abstract] [Hide abstract] ABSTRACT: Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that prevent the aggregation of unfolding proteins during proteotoxic stress. In Caenorhabditis elegans, Sip1 is the only sHsp exclusively expressed in oocytes and embryos. Here, we demonstrate that Sip1 is essential for heat shock survival of reproducing adults and embryos. X-ray crystallography and electron microscopy revealed that Sip1 exists in a range of well-defined globular assemblies consisting of two half-spheres, each made of dimeric "spokes." Strikingly, the oligomeric distribution of Sip1 as well as its chaperone activity depend on pH, with a trend toward smaller species and higher activity at acidic conditions such as present in nematode eggs. The analysis of the interactome shows that Sip1 has a specific substrate spectrum including proteins that are essential for embryo development. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · May 2015 · Molecular cell
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    • "Under transcriptional regulation of the heat shock factor, Hsf1, levels of sHSPs can rise to 1% of total cellular protein when conditions deviate from the norm, e.g. ischemia, hypoxia, oncogene activation, and chemotherapy (Kampinga and Garrido, 2012). sHSPs are found throughout prokaryotes and eukaryotes. "
    [Show abstract] [Hide abstract] ABSTRACT: Small heat shock proteins (sHSPs) are essential 'holdase' chaperones that form large assemblies and respond dynamically to pH and temperature stresses to protect client proteins from aggregation. While the alpha-crystallin domain (ACD) dimer of sHSPs is the universal building block, how the ACD transmits structural changes in response to stress to promote holdase activity is unknown. We found that the dimer interface of HSPB5 is destabilized over physiological pHs and a conserved histidine (His-104) controls interface stability and oligomer structure in response to acidosis. Destabilization by pH or His-104 mutation shifts the ACD from dimer to monomer but also results in a large expansion of HSPB5 oligomer states. Remarkably, His-104 mutant-destabilized oligomers are efficient holdases that reorganize into structurally distinct client-bound complexes. Our data support a model for sHSP function wherein cell stress triggers small perturbations that alter the ACD building blocks to unleash a cryptic mode of chaperone action.
    Full-text · Article · May 2015 · eLife Sciences
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