Journal of Molecular Biology
ReviewBiP and Its Nucleotide Exchange Factors Grp170 and Sil1: Mechanisms of Action and Biological Functions
Graphical abstract
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.
References (196)
- et al.
Life and death of a BiP substrate
Semin Cell Dev Biol
(2010) - et al.
BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP
J Biol Chem
(2002) - et al.
Biochemical characterization of the mammalian stress proteins and identification of two stress proteins as glucose- and Ca2Ā +-ionophore-regulated proteins
J Biol Chem
(1983) - et al.
Calcium-dependent autophosphorylation of the glucose-regulated protein, Grp78
Arch Biochem Biophys
(1991) - et al.
Modulation of the phosphorylation of glucose-regulated protein, GRP78, by transformation and inhibition of glycosylation
Exp Cell Res
(1993) - et al.
Peptide-dependent stimulation of the ATPase activity of the molecular chaperone BiP is the result of conversion of oligomers to active monomers
J Biol Chem
(1993) - et al.
Unfolded protein response-regulated Drosophila Fic (dFic) protein reversibly AMPylates BiP chaperone during endoplasmic reticulum homeostasis
J Biol Chem
(2014) - et al.
Translocation of ATP into the lumen of rough endoplasmic reticulum-derived vesicles and its binding to luminal proteins including BiP (GRP 78) and GRP 94
J Biol Chem
(1992) - et al.
An Hsp70-like protein in the ER: identity with the 78 kD glucose-regulated protein and immunoglobulin heavy chain binding protein
Cell
(1986) - et al.
Molecular chaperones and protein quality control
Cell
(2006)
Gymnastics of molecular chaperones
Mol Cell
The changing landscape of protein allostery
Curr Opin Struct Biol
Amide hydrogen exchange reveals conformational changes in hsp70 chaperones important for allosteric regulation
J Biol Chem
Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker
Mol Cell
Allosteric regulation of Hsp70 chaperones by a proline switch
Mol Cell
In vitro dissociation of BiP-peptide complexes requires a conformational change in BiP after ATP binding but does not require ATP hydrolysis
J Biol Chem
Allosteric regulation of Hsp70 chaperones involves a conserved interdomain linker
J Biol Chem
Structural basis of interdomain communication in the Hsc70 chaperone
Mol Cell
The conformational dynamics of the mitochondrial Hsp70 chaperone
Mol Cell
How potassium affects the activity of the molecular chaperone Hsc70. II. Potassium binds specifically in the ATPase active site
J Biol Chem
Structure and dynamics of the ATP-bound open conformation of Hsp70 chaperones
Mol Cell
Hsp70 chaperone dynamics and molecular mechanism
Trends Biochem Sci
Modulation of the ATPase cycle of BiP by peptides and proteins
J Mol Biol
Crystal structures of the 70-kDa heat shock proteins in domain disjoining conformation
J Biol Chem
ER quality control in the biogenesis of MHC class I molecules
Semin Cell Dev Biol
BiP maintains the permeability barrier of the ER membrane by sealing the lumenal end of the translocon pore before and early in translocation
Cell
ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals
Dev Cell
Conserved, disordered C terminus of DnaK enhances cellular survival upon stress and DnaK in vitro chaperone activity
J Biol Chem
An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones
Cell
BiP acts as a molecular ratchet during posttranslational transport of prepro-alpha factor across the ER membrane
Cell
Structural basis of J cochaperone binding and regulation of Hsp70
Mol Cell
Mutations within the nucleotide binding site of immunoglobulin-binding protein inhibit ATPase activity and interfere with release of immunoglobulin heavy chain
J Biol Chem
Characterization of the nucleotide binding properties and ATPase activity of recombinant hamster BiP purified from bacteria
J Biol Chem
The affinity of a major Ca2Ā + binding site on GRP78 is differentially enhanced by ADP and ATP
J Biol Chem
Unassembled Ig heavy chains do not cycle from BiP in vivo but require light chains to trigger their release
Immunity
Sls1p, an endoplasmic reticulum component, is involved in the protein translocation process in the yeast Yarrowia lipolytica
J Biol Chem
Interaction of Kar2p and Sls1p is required for efficient co-translational translocation of secreted proteins in the yeast Yarrowia lipolytica
J Biol Chem
HspBP1, a homologue of the yeast Fes1 and Sls1 proteins, is an Hsc70 nucleotide exchange factor
FEBS Lett
Inhibition of Hsp70 ATPase activity and protein renaturation by a novel Hsp70-binding protein
J Biol Chem
Regulation of Hsp70 function by HspBP1: structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange
Mol Cell
Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation
Cell
A C-terminal signal prevents secretion of luminal ER proteins
Cell
C-terminal mutations destabilize SIL1/BAP and can cause Marinesco-Sjogren syndrome
J Biol Chem
The 170Ā kDa glucose regulated stress protein is a large HSP70-, HSP110-like protein of the endoplasmic reticulum
FEBS Lett
Role of N-linked oligosaccharide recognition, glucose trimming, and calnexin in glycoprotein folding and quality control
Proc Natl Acad Sci U S A
Chaperone selection during glycoprotein translocation into the endoplasmic reticulum
Science
Co-chaperones of the mammalian endoplasmic reticulum
Subcell Biochem
Coordinated activation of Hsp70 chaperones
Science
ADP-ribosylation of the Mr 83,000 stress-inducible and glucose-regulated protein in avian and mammalian cells: modulation by heat shock and glucose starvation
Proc Natl Acad Sci U S A
Identity of the immunoglobulin heavy-chain-binding protein with the 78,000-dalton glucose-regulated protein and the role of posttranslational modifications in its binding function
Mol Cell Biol
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J.B. and M.J.F. contributed equally to this work.