Vigilin interacts with signal peptide peptidase

Lu, Stephen Hsueh-Jeng; Jeon, Amy Hye Won; Schmitt‐Ulms, Gerold; Qamar, Seema; Dodd, Roger B.; McDonald, Beth M.; Li, Yi; Meadows, William; Cox, Katie; Böhm, Christopher; Chen, Fusheng; Fraser, Paul E.; George-Hyslop, Peter St

doi:10.1186/1477-5956-10-33

Cited by 3 publications

(3 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These complexes with a molecular weight two to three times larger than that of the homotetrameric complex seem to differ in regard to substrate binding and binding of misfolded/unfolded proteins [57]. Recently, in a proteomic analysis of SPP binding partners, vigilin, a cytoplasmic protein involved in RNA binding and protein translation control, was found to interact with SPP in a high molecular weight complex, yet it did not alter or affect proteolytic activity of SPP [84]. This may indicate that SPP (and possibly SPPLs) forms high molecular weight complexes with additional binding partners that, though they do not to affect proteolytic activity, contribute to possible non-proteolytic functions of SPP/SPPLs.…”

Section: Structure and Topology Of Spp/spplsmentioning

confidence: 99%

Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases

Voß

Schröder

Fluhrer

2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

121

155

View full text Add to dashboard Cite

Signal peptide peptidase (SPP) and the homologous SPP-like (SPPL) proteases SPPL2a, SPPL2b, SPPL2c and SPPL3 belong to the family of GxGD intramembrane proteases. SPP/SPPLs selectively cleave transmembrane domains in type II orientation and do not require additional co-factors for proteolytic activity. Orthologues of SPP and SPPLs have been identified in other vertebrates, plants, and eukaryotes. In line with their diverse subcellular localisations ranging from the ER (SPP, SPPL2c), the Golgi (SPPL3), the plasma membrane (SPPL2b) to lysosomes/late endosomes (SPPL2a), the different members of the SPP/SPPL family seem to exhibit distinct functions. Here, we review the substrates of these proteases identified to date as well as the current state of knowledge about the physiological implications of these proteolytic events as deduced from in vivo studies. Furthermore, the present knowledge on the structure of intramembrane proteases of the SPP/SPPL family, their cleavage mechanism and their substrate requirements are summarised. This article is part of a Special Issue entitled: Intramembrane Proteases.

show abstract

Section: Structure and Topology Of Spp/spplsmentioning

confidence: 99%

Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases

Voß

Schröder

Fluhrer

2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

121

155

View full text Add to dashboard Cite

show abstract

“…Presenilin PS1 (and PS2) are the catalytic subunits of the heterotetrameric presenilin 1 (or presenilin 2) complexes (Wolfe et al 1999b;Li et al 2000a;Chen et al 2006;Ahn et al 2010) and are the founding members of the GXGD family of intramembranous aspartyl proteases. Other members of this protease family include signal peptide peptidases (SPP) and a variety of archaeal homologs (Weihofen et al 2002;Martoglio and Golde 2003;Friedmann et al 2004;Fluhrer et al 2009;Lu et al 2012a). These proteins will not be discussed in detail here except to note that they are monomeric or dimeric, and they have an opposite topology to the membrane relative to the presenilin proteins.…”

Section: Topology and Structure Of Presenilin-complex Components Presmentioning

confidence: 99%

Structural and Chemical Biology of Presenilin Complexes

Johnson

Pettersson

et al. 2017

Cold Spring Harb Perspect Med

View full text Add to dashboard Cite

The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the γ, ɛ, ζ site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme. Taken together, these studies suggest that the complex exists in several conformations, and subtle long-range (allosteric) shifts in the conformation of the complex underpin substrate access to the catalytic site and the mechanism of action for allosteric inhibitors and modulators. Understanding the mechanics of these shifts will facilitate the design of γ-secretase modulator (GSM) compounds that modulate the relative efficiency of γ, ɛ, ζ site cleavage and/or substrate specificity.

show abstract

“…PS1 (and PS2) are the catalytic subunits of the heterotetrameric presenilin 1 (or presenilin 2) complexes [ 29 , 31 ] and are the archetypal members of the GXGD family of intramembranous aspartyl proteases, which also includes signal peptide peptidases (SPP) and a variety of archaeal homologues [ 38 – 42 ].…”

Section: Introductionmentioning

confidence: 99%

Structural biology of presenilin 1 complexes

Böhm

Dodd

et al. 2014

Mol Neurodegeneration

Self Cite

View full text Add to dashboard Cite

The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease. Subsequent work has shown that the presenilin proteins are the catalytic subunits of a hetero-tetrameric complex containing APH1, nicastrin and PEN-2. This complex (variously termed presenilin complex or gamma-secretase complex) performs an unusual type of proteolysis in which the transmembrane domains of Type I proteins are cleaved within the hydrophobic compartment of the membrane. This review describes some of the molecular and structural biology of this unusual enzyme complex. The presenilin complex is a bilobed structure. The head domain contains the ectodomain of nicastrin. The base domain contains a central cavity with a lateral cleft that likely provides the route for access of the substrate to the catalytic cavity within the centre of the base domain. There are reciprocal allosteric interactions between various sites in the complex that affect its function. For instance, binding of Compound E, a peptidomimetic inhibitor to the PS1 N-terminus, induces significant conformational changes that reduces substrate binding at the initial substrate docking site, and thus inhibits substrate cleavage. However, there is a reciprocal allosteric interaction between these sites such that prior binding of the substrate to the initial docking site paradoxically increases the binding of the Compound E peptidomimetic inhibitor. Such reciprocal interactions are likely to form the basis of a gating mechanism that underlies access of substrate to the catalytic site. An increasingly detailed understanding of the structural biology of the presenilin complex is an essential step towards rational design of substrate- and/or cleavage site-specific modulators of presenilin complex function.

show abstract

Vigilin interacts with signal peptide peptidase

Cited by 3 publications

References 23 publications

Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases

Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases

Structural and Chemical Biology of Presenilin Complexes

Structural biology of presenilin 1 complexes

Contact Info

Product

Resources

About