Substrate Requirements for SPPL2b-dependent Regulated Intramembrane Proteolysis

Martin, Lucas; Fluhrer, Regina; Haass, Christian

doi:10.1074/jbc.m807485200

Cited by 53 publications

(73 citation statements)

References 46 publications

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“…Given its molecular mass, it is very likely that the luminal domain of ICD(L3) is significantly shorter than that of LP18. Therefore, our results are in line with the previous observation that SPPL2b most efficiently cleaves Bri2 substrates with an ectodomain shorter than 23 amino acids (10). We cannot, however, completely rule out that, for example, different subcellular localizations of LP18 and ICD(L3) favor a more efficient turnover of the latter by SPPL2a/2b.…”

Section: Discussionsupporting

confidence: 81%

“…In contrast to all SPPL substrates described so far (3), FVenv is cleaved not only by SPPL2a/b but also by SPPL3. In line with previous studies (10), cleavage of FVenv by overexpressed SPPL2a/b is dependent on PC-mediated cleavage, which precedes the intramembrane cleavage and generates LP18, a single-span transmembrane protein with a short ectodomain (Fig. 5A).…”

Section: Discussionsupporting

confidence: 66%

“…In accordance with previous studies (10,35), SPPL2a and SPPL2b only accept FVenv species with a type II membrane orientation and a truncated luminal domain as their substrates. Both LP18 generated by PC cleavage of FVenv and ICD(L3) generated by SPPL3 cleavage of FVenv fulfill this criteria and are cleaved by SPPL2a/b to generate ICD(L2) (Fig.…”

Section: Discussionsupporting

confidence: 55%

“…Initial shedding is known to be required for SPPL2b-mediated intramembrane proteolysis (10). In line with this, ICD(L2) production correlated with the reduction of LP18 upon coexpression of SPPL2b and FVenv mut (Fig.…”

Section: Fvenv Is Proteolytically Processed By Sppl Proteases-fvenvsupporting

confidence: 60%

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Foamy Virus Envelope Protein Is a Substrate for Signal Peptide Peptidase-like 3 (SPPL3)

Voß

Fukumori

Kuhn

et al. 2012

Journal of Biological Chemistry

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Background: SPPL proteases are intramembrane-cleaving aspartyl proteases of the GxGD type. Results: Under certain circumstances, SPPL3 cleaves FVenv independent of prior shedding, generating substrates for subsequent intramembrane proteolysis. Conclusion: Unlike other known GxGD proteases, SPPL3 can act as a sheddase and an intramembrane protease within the regulated intramembrane proteolysis cascade. Significance: This initial biochemical characterization of SPPL3 will help to address its physiological role in later studies.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 66%

Section: Discussionsupporting

confidence: 55%

Section: Fvenv Is Proteolytically Processed By Sppl Proteases-fvenvsupporting

confidence: 60%

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Foamy Virus Envelope Protein Is a Substrate for Signal Peptide Peptidase-like 3 (SPPL3)

Voß

Fukumori

Kuhn

et al. 2012

Journal of Biological Chemistry

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“…Little is known about the biological function of NCT, APH-1, and PEN-2. NCT is probably required as a sizeselecting substrate receptor (Shah et al 2005;Dries et al 2009), although recent findings may challenge such a function (Chavez-Gutierrez et al 2008;Martin et al 2009). PEN-2 apparently facilitates PS endoproteolysis into its active heterodimeric state and stabilizes PS within the g-secretase complex (Hasegawa et al 2004;Prokop et al 2004).…”

Section: G-secretasementioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

890

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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ATP‐independent molecular chaperone activity generated under reducing conditions

et al. 2022

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Molecular chaperones are essential to maintain proteostasis. While the functions of intracellular molecular chaperones that oversee protein synthesis, folding and aggregation, are established, those specialized to work in the extracellular environment are less understood. Extracellular proteins reside in a considerably more oxidizing milieu than cytoplasmic proteins and are stabilized by abundant disulfide bonds. Hence, extracellular proteins are potentially destabilized and sensitive to aggregation under reducing conditions. We combine biochemical and mass spectrometry experiments and elucidate that the molecular chaperone functions of the extracellular protein domain Bri2 BRICHOS only appear under reducing conditions, through the assembly of monomers into large polydisperse oligomers by an intra‐ to intermolecular disulfide bond relay mechanism. Chaperone‐active assemblies of the Bri2 BRICHOS domain are efficiently generated by physiological thiol‐containing compounds and proteins, and appear in parallel with reduction‐induced aggregation of extracellular proteins. Our results give insights into how potent chaperone activity can be generated from inactive precursors under conditions that are destabilizing to most extracellular proteins and thereby support protein stability/folding in the extracellular space. Significance Chaperones are essential to cells as they counteract toxic consequences of protein misfolding particularly under stress conditions. Our work describes a novel activation mechanism of an extracellular molecular chaperone domain, called Bri2 BRICHOS. This mechanism is based on reducing conditions that initiate small subunits to assemble into large oligomers via a disulfide relay mechanism. Activated Bri2 BRICHOS inhibits reduction‐induced aggregation of extracellular proteins and could be a means to boost proteostasis in the extracellular environment upon reductive stress.

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Substrate Requirements for SPPL2b-dependent Regulated Intramembrane Proteolysis

Cited by 53 publications

References 46 publications

Foamy Virus Envelope Protein Is a Substrate for Signal Peptide Peptidase-like 3 (SPPL3)

Foamy Virus Envelope Protein Is a Substrate for Signal Peptide Peptidase-like 3 (SPPL3)

Trafficking and Proteolytic Processing of APP

ATP‐independent molecular chaperone activity generated under reducing conditions

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