Journal of Molecular Biology
Volume 427, Issue 7, 10 April 2015, Pages 1589-1608
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Review
BiP and Its Nucleotide Exchange Factors Grp170 and Sil1: Mechanisms of Action and Biological Functions

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Highlights

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    Structural and mechanistic insights into the Hsp70 ATPase cycle are reviewed.

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    The influence of the ER environment on the ATPase cycle of BiP is discussed.

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    Mechanisms of nucleotide exchange in BiP by Sil1 and Grp170 are reviewed.

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    Our current understanding of the Grp170 chaperone function is presented.

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    Biological functions and associated pathologies of Sil1 and Grp170 are reviewed.

Abstract

BiP (immunoglobulin heavy-chain binding protein) is the endoplasmic reticulum (ER) orthologue of the Hsp70 family of molecular chaperones and is intricately involved in most functions of this organelle through its interactions with a variety of substrates and regulatory proteins. Like all Hsp70 family members, the ability of BiP to bind and release unfolded proteins is tightly regulated by a cycle of ATP binding, hydrolysis, and nucleotide exchange. As a characteristic of the Hsp70 family, multiple DnaJ-like co-factors can target substrates to BiP and stimulate its ATPase activity to stabilize the binding of BiP to substrates. However, only in the past decade have nucleotide exchange factors for BiP been identified, which has shed light not only on the mechanism of BiP-assisted folding in the ER but also on Hsp70 family members that reside throughout the cell. We will review the current understanding of the ATPase cycle of BiP in the unique environment of the ER and how it is regulated by the nucleotide exchange factors, Grp170 (glucose-regulated protein of 170Ā kDa) and Sil1, both of which perform unanticipated roles in various biological functions and disease states.

Section snippets

Protein Folding and Quality Control in the ER

Approximately one-third of the human genome encodes proteins that reside at the cell surface, that are secreted, or that populate organelles of the secretory pathway. These proteins are synthesized at the endoplasmic reticulum (ER) membrane and are translocated into the lumen where they acquire their functional tertiary and quaternary structure. The folding of these proteins and their assembly into larger heteromeric complexes is guided by the same principles and processes used throughout the

A resting state of BiP

Changes in the external environment or different developmental stages of a cell can result in large variations in the load of unfolded or misfolded proteins in the ER. BiP as one of the major ER chaperones must therefore be readily and rapidly available in times of need. Differentially modified and assembled forms of BiP seem to be present in the ER to cope with altering cellular conditions. In the absence of stress, BiP has been shown to be a major ADP-ribosylated protein in mammalian cells [7]

The identification of a NEF for the ER lumenal Hsp70

Although BiP's ATPase cycle would appear to be particularly dependent on co-factors to regulate its binding and release from substrates, no resident ER proteins that possessed nucleotide exchange activity had been identified in any organism until the late 1990s (see Fig.Ā 3 for an overview of cytosolic and ER lumenal Hsp70 NEFs; cytosolic Hsp70 NEFs are reviewed in Ref. [77]). Then several laboratories independently identified the first BiP NEF in three different organisms. Sls1p was identified

Grp170: A NEF with a Chaperone Function

In addition to Sil1, a second NEF for BiP has been identified, Grp170. Based on similarities in domain organization, it was assigned to the family of large Hsp70s [100], [101], [102], which constitute the Hsp70 superfamily together with the conventional Hsp70s (Fig.Ā 3). Although BiP and Grp170 share structural similarities, in contrast to BiP, where much is known about its various functions and how they are regulated [103], we are still lacking a clear understanding of Grp170's functions in the

Cellular functions dependent on Sil1

While the ER functions that Sil1 participates in remain rather poorly understood, some insights have been obtained by examining the effects of gene disruption in organisms ranging from yeast to man. In humans, mutations in the SIL1 gene have been found in over half the cases of Marinesco-Sjƶgren syndrome (MSS) [152], [153], [154], an autosomal recessive disease characterized by multisystem defects including cerebellar ataxia due to Purkinje cell loss, progressive myopathy, early-onset

Concluding Thoughts

While the past decade has significantly increased our understanding of how the ATPase cycle of BiP is regulated, this information has led to many more questions. First, it is unclear what the relative contributions of Sil1 and Grp170 are to BiP's requirement for exchange activity, how exchange activity contributes to the various biological functions of BiP, and whether this differs in individual tissues or under various developmental or stress conditions. Mechanistically, it is not completely

Acknowledgements

J.B. gratefully acknowledges funding by the Boehringer Ingelheim Fonds; M.J.F., by the German Academy of Sciences Leopoldina Grant Number LPDS 2009-32; and L.M.H., by the National Institutes of Health Grant Number R01 GM054068.

Conflict of Interest Statement: The authors declare no competing financial interests.

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    J.B. and M.J.F. contributed equally to this work.

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