BiP and Its Nucleotide Exchange Factors Grp170 and Sil1: Mechanisms of Action and Biological Functions

Behnke, Julia; Feige, Matthias J.; Hendershot, Linda M.

doi:10.1016/j.jmb.2015.02.011

Cited by 165 publications

(179 citation statements)

References 194 publications

(316 reference statements)

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“…Next we analyzed how the other major chaperone system of the ER, the Hsp70 system centered around BiP (36), recognized the TCR ␣ and ␤ chains. In agreement with data published previously (10,34,35) we found both ␣ RK-ϾLL and ␤ K-ϾL to be BiP substrates (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dimerization-dependent Folding Underlies Assembly Control of the Clonotypic αβT Cell Receptor Chains

Feige¹,

Behnke²,

Mittag

et al. 2015

Journal of Biological Chemistry

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Background: Assembly of heteromeric membrane protein complexes is monitored prior to their transport to the cell surface. Results: Each of the ␣␤TCR clonotypic chains comprises one domain that folds upon assembly. Conclusion: Proper ␣␤TCR biogenesis is scrutinized by assembly-coupled folding steps. Significance: This study shows how the assembly of heteromeric membrane proteins can be monitored and indicates limitations of the possible T cell repertoire.

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Section: Resultsmentioning

confidence: 99%

Dimerization-dependent Folding Underlies Assembly Control of the Clonotypic αβT Cell Receptor Chains

Feige¹,

Behnke²,

Mittag

et al. 2015

Journal of Biological Chemistry

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“…Here we demonstrate that the ER luminal chaperone Grp170, an atypical member of the Hsp70 superfamily (14), promotes the degradation of Akita proinsulin. We show that Grp170 shifts the balance of high-MW oligomers bearing Akita proinsulin toward smaller oligomeric species that are capable of undergoing ERAD.…”

Section: Introductionmentioning

confidence: 84%

Chaperone-Driven Degradation of a Misfolded Proinsulin Mutant in Parallel With Restoration of Wild-Type Insulin Secretion

Cunningham

Arunagiri

et al. 2016

Diabetes

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In heterozygous patients with a diabetic syndrome called mutant INS gene–induced diabetes of youth (MIDY), there is decreased insulin secretion when mutant proinsulin expression prevents wild-type (WT) proinsulin from exiting the endoplasmic reticulum (ER), which is essential for insulin production. Our previous results revealed that mutant Akita proinsulin is triaged by ER-associated degradation (ERAD). We now find that the ER chaperone Grp170 participates in the degradation process by shifting Akita proinsulin from high–molecular weight (MW) complexes toward smaller oligomeric species that are competent to undergo ERAD. Strikingly, overexpressing Grp170 also liberates WT proinsulin, which is no longer trapped in these high-MW complexes, enhancing ERAD of Akita proinsulin and restoring WT insulin secretion. Our data reveal that Grp170 participates in preparing mutant proinsulin for degradation while enabling WT proinsulin escape from the ER. In principle, selective destruction of mutant proinsulin offers a rational approach to rectify the insulin secretion problem in MIDY.

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“…BiP serves several fundamental roles that together work to maintain ER homeostasis (for recent reviews see [4, 5]). BiP plays an early role in secretory protein biogenesis; BiP binds nascent polypeptide chains to facilitate their translocation across the ER membrane [6, 7].…”

Section: Introductionmentioning

confidence: 99%

A Conserved Cysteine within the ATPase Domain of the Endoplasmic Reticulum Chaperone BiP is Necessary for a Complete Complement of BiP Activities

Marsh

Sevier

2016

Journal of Molecular Biology

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Among the amino acids, cysteine stands apart based on its highly reactive sulfur group. In general, cysteine is underrepresented in proteins. Yet when present, the features of cysteine often afford unique function. We have shown previously that a cysteine within the ATPase domain of yeast BiP (Kar2) serves as a sensor of the endoplasmic reticulum (ER) redox environment [1, 2]. Under conditions of increased oxidant (oxidative stress) this cysteine becomes oxidized, changing Kar2 from an ATP-dependent foldase to an ATP-independent holdase. We were struck by the high degree of conservation for this cysteine between BiP orthologs, and we sought to determine how cysteine substitution impacts Kar2 function. We observed no single amino acid replacement is capable of recreating the range of functions that can be achieved by wild-type Kar2 with its cysteine in either the unmodified or oxidized states. However, we were able to generate mutants that could selectively replicate the distinct activities exhibited by either unmodified or oxidized Kar2. We found that the ATPase activity displayed by unmodified Kar2 is fully maintained when Cys63 is replaced with Ala or Val. Conversely, we demonstrate that several amino acid substitutions (including His, Phe, Pro, Trp, Tyr) support an enhanced viability during oxidative stress associated with oxidized Kar2, although these alleles are compromised as an ATPase. We reveal the range of activity demonstrated by wild-type Kar2 can be replicated by co-expression of Kar2 mutants that mimic either the unmodified or oxidized Kar2 state, allowing for growth during standard and oxidative stress conditions.

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BiP and Its Nucleotide Exchange Factors Grp170 and Sil1: Mechanisms of Action and Biological Functions

Cited by 165 publications

References 194 publications

Dimerization-dependent Folding Underlies Assembly Control of the Clonotypic αβT Cell Receptor Chains

Dimerization-dependent Folding Underlies Assembly Control of the Clonotypic αβT Cell Receptor Chains

Chaperone-Driven Degradation of a Misfolded Proinsulin Mutant in Parallel With Restoration of Wild-Type Insulin Secretion

A Conserved Cysteine within the ATPase Domain of the Endoplasmic Reticulum Chaperone BiP is Necessary for a Complete Complement of BiP Activities

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