Gamma secretase

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Gamma-secretase (Nicastrin subunit)
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The gamma secretase complex, with nicastrin (red), presenilin-1 (orange), PEN-2 (blue), and APH-1 (green); lumenal membrane shown in red and cytoplasmic membrane shown in blue. The structure was solved by cryo-electron microscopy. [1]
Identifiers
SymbolGamma-secretase, γ-secretase
Pfam PF05450
InterPro IPR008710
OPM superfamily 244
OPM protein [ 5fn5[
Membranome 155
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Gamma secretase is a multi-subunit protease complex, an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43[ verification needed ] amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, [2] ErbB4, [3] E-cadherin, [4] N-cadherin, [5] ephrin-B2, [6] or CD44. [7]

Contents

Subunits and assembly

The gamma secretase complex consists of four individual proteins: PSEN1 (presenilin-1), [8] nicastrin, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2). [9] Recent evidence suggests that a fifth protein, known as CD147, is a non-essential regulator of the complex whose absence increases activity. [10] [11] Presenilin, an aspartyl protease, is the catalytic subunit; mutations in the presenilin gene a major genetic risk factor for Alzheimer's disease [12] and modulates immune cell activity. [13] In humans, two forms of presenilin and two forms of APH-1 have been identified in the genome; one of the APH homologs can also be expressed in two isoforms via alternative splicing, leading to at least six different possible gamma secretase complexes that may have tissue- or cell type specificity. [14]

The proteins in the gamma secretase complex are heavily modified by proteolysis during assembly and maturation of the complex; a required activation step is in the autocatalytic cleavage of presenilin to N- and C-terminal fragments. Nicastrin's primary role is in maintaining the stability of the assembled complex and regulating intracellular protein trafficking. [15] PEN-2 associates with the complex via binding of a transmembrane domain of presenilin [16] and, among other possible roles, helps to stabilize the complex after presenilin proteolysis has generated the activated N-terminal and C-terminal fragments. [17] APH-1, which is required for proteolytic activity, binds to the complex via a conserved alpha helix interaction motif and aids in initiating assembly of premature components. [18]

Recent research has shown that the interaction of the gamma secretase complex with the γ-secretase activating protein facilitates the gamma cleavage of amyloid precursor protein into β-amyloid. [19]

Cellular trafficking

The gamma secretase complex is thought to assemble and mature via proteolysis in the early endoplasmic reticulum. [20] The complexes are then transported to the late ER where they interact with and cleave their substrate proteins. [21] Gamma secretase complexes have also been observed localized to the mitochondria, where they may play a role in promoting apoptosis. [22]

Function

Gamma secretase is an internal protease that cleaves within the membrane-spanning domain of its substrate proteins, including amyloid precursor protein (APP) and Notch. Substrate recognition occurs via nicastrin ectodomain binding to the N-terminus of the target, which is then passed via a poorly understood process between the two presenilin fragments to a water-containing active site where the catalytic aspartate residue is located. The active site must contain water to carry out hydrolysis within a hydrophobic environment in the interior of the cell membrane, although it is not well understood how water and proton exchange is effected, and as yet no X-ray crystallography structure of gamma secretase is available. [23] Low-resolution electron microscopy reconstructions have allowed the visualization of the hypothesized internal pores of about 2 nanometres. [24] In 2014, a three-dimensional structure of an intact human gamma-secretase complex was determined by cryo-electron microscopy single-particle analysis at 4.5 angstrom resolution [25] and in 2015 an atomic-resolution (3.4 angstrom) cryo-EM structure was reported. [1]

The gamma secretase complex is unusual among proteases in having a "sloppy" cleavage site at the C-terminal site in amyloid beta generation; gamma secretase can cleave APP in any of multiple sites to generate a peptide of variable length, most typically from 39 to 42 amino acids long, with Aβ40 the most common isoform and Aβ42 the most susceptible to conformational changes leading to amyloid fibrillogenesis. Certain mutations in both APP and both types of human presenilin are associated with increased Aβ42 production and the early-onset genetic form of familial Alzheimer's disease. [26] Although older data suggested that different forms of the gamma secretase complex could be differentially responsible for generating different amyloid beta isoforms, [27] current evidence indicates that the C-terminus of amyloid beta is produced by a series of single-residue cleavages by the same gamma secretase complex. [28] [29] [30] Earlier cleavage sites produce peptides of length 46 (zeta-cleavage) and 49 (epsilon-cleavage). [29]

See also

Related Research Articles

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Both neurons and oligodendrocytes produce and release Aβ in the brain. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in humans

Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

<span class="mw-page-title-main">Amyloid-beta precursor protein secretase</span> Type of enzyme

Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane.

<span class="mw-page-title-main">Beta-secretase 1</span> Enzyme

Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene. Expression of BACE1 is observed mainly in neurons and oligodendrocytes.

In molecular biology, the Signal Peptide Peptidase (SPP) is a type of protein that specifically cleaves parts of other proteins. It is an intramembrane aspartyl protease with the conserved active site motifs 'YD' and 'GxGD' in adjacent transmembrane domains (TMDs). Its sequences is highly conserved in different vertebrate species. SPP cleaves remnant signal peptides left behind in membrane by the action of signal peptidase and also plays key roles in immune surveillance and the maturation of certain viral proteins.

<span class="mw-page-title-main">Presenilin</span>

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop. Vertebrates have two presenilin genes, called PSEN1 that codes for presenilin 1 (PS-1) and PSEN2 that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.

<span class="mw-page-title-main">Alpha secretase</span> Family of proteolytic enzymes

Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase. The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM family, which are expressed on the surfaces of cells and anchored in the cell membrane. Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding.

<span class="mw-page-title-main">Nicastrin</span>

Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the NCSTN gene.

APH-1 is a protein gene product originally identified in the Notch signaling pathway in Caenorhabditis elegans as a regulator of the cell-surface localization of nicastrin. APH-1 homologs in other organisms, including humans, have since been identified as components of the gamma secretase complex along with the catalytic subunit presenilin and the regulatory subunits nicastrin and PEN-2. The gamma-secretase complex is a multimeric protease responsible for the intramembrane proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). Gamma-secretase cleavage of APP is one of two proteolytic steps required to generate the peptide known as amyloid beta, whose misfolded form is implicated in the causation of Alzheimer's disease. All of the components of the gamma-secretase complex undergo extensive post-translational modification, especially proteolytic activation; APH-1 and PEN-2 are regarded as regulators of the maturation process of the catalytic component presenilin. APH-1 contains a conserved alpha helix interaction motif glycine-X-X-X-glycine (GXXXG) that is essential to both assembly of the gamma secretase complex and to the maturation of the components.

<span class="mw-page-title-main">PEN-2</span> Protein-coding gene in the species Homo sapiens

PSENEN, formally PEN-2, is a protein that is a regulatory component of the gamma secretase complex, a protease complex responsible for proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). The gamma secretase complex consists of PEN-2, APH-1, nicastrin, and the catalytic subunit presenilin. PEN-2 is a 101-amino acid integral membrane protein likely with a topology such that both the N-terminus and the C-terminus face first the lumen of the endoplasmic reticulum and later the extracellular environment. Biochemical studies have shown that a conserved sequence motif D-Y-L-S-F at the C-terminus, as well as the overall length of the C-terminal tail, is required for the formation of an active gamma secretase complex.

<span class="mw-page-title-main">Presenilin-1</span> Protein-coding gene in the species Homo sapiens

Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.

<span class="mw-page-title-main">Caspase 6</span> Enzyme found in humans

Caspase-6 is an enzyme that in humans is encoded by the CASP6 gene. CASP6 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts. Caspase-6 has known functions in apoptosis, early immune response and neurodegeneration in Huntington's and Alzheimer's disease.

<span class="mw-page-title-main">PSEN2</span> Protein-coding gene in the species Homo sapiens

Presenilin-2 is a protein that is encoded by the PSEN2 gene.

<span class="mw-page-title-main">APLP1</span> Protein-coding gene in the species Homo sapiens

Amyloid-like protein 1, also known as APLP1, is a protein that in humans is encoded by the APLP1 gene. APLP1 along with APLP2 are important modulators of glucose and insulin homeostasis.

<span class="mw-page-title-main">APBA2</span> Protein-coding gene in the species Homo sapiens

Amyloid beta A4 precursor protein-binding family A member 2 is a protein that in humans is encoded by the APBA2 gene.

<span class="mw-page-title-main">HM13</span> Protein-coding gene in the species Homo sapiens

Minor histocompatibility antigen H13 is a protein that in humans is encoded by the HM13 gene.

<span class="mw-page-title-main">UNQ1887</span> Protein-coding gene in the species Homo sapiens

Signal peptide peptidase 3, also known as UNQ1887, is a human gene.

<span class="mw-page-title-main">SPPL2B</span> Protein-coding gene in the species Homo sapiens

Signal peptide peptidase-like 2B, also known as SPPL2B, is a human gene.

<span class="mw-page-title-main">SPPL2A</span> Protein-coding gene in the species Homo sapiens

Signal peptide peptidase-like 2A, also known as SPPL2A, is a human gene.

Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral membrane proteins with multiple transmembrane domains, and they have their active sites buried within the lipid bilayer of cellular membranes. Intramembrane proteases are responsible for proteolytic cleavage in the cell signaling process known as regulated intramembrane proteolysis (RIP).

References

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  19. ↑ He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (September 2010). "Gamma-secretase activating protein, a therapeutic target for Alzheimer's disease". Nature. 467 (2): 95–98. doi:10.1038/nature09325. PMC   2936959 . PMID   20811458.
  20. ↑ Capell A, Beher D, Prokop S, Steiner H, Kaether C, Shearman MS, Haass C (February 2005). "Gamma-secretase complex assembly within the early secretory pathway". J. Biol. Chem. 280 (8): 6471–8. doi: 10.1074/jbc.M409106200 . PMID   15591316.
  21. ↑ Kim SH, Yin YI, Li YM, Sisodia SS (November 2004). "Evidence that assembly of an active gamma-secretase complex occurs in the early compartments of the secretory pathway". J. Biol. Chem. 279 (47): 48615–9. doi: 10.1074/jbc.C400396200 . PMID   15456788.
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  28. ↑ Zhao G, Tan J, Mao G, Cui MZ, Xu X (March 2007). "The same gamma-secretase accounts for the multiple intramembrane cleavages of APP". J. Neurochem. 100 (5): 1234–46. doi: 10.1111/j.1471-4159.2006.04302.x . PMID   17241131.
  29. 1 2 Zhang, H; Ma, Q; Zhang, YW; Xu, H (January 2012). "Proteolytic processing of Alzheimer's β-amyloid precursor protein". Journal of Neurochemistry. 120 Suppl 1: 9–21. doi:10.1111/j.1471-4159.2011.07519.x. PMC   3254787 . PMID   22122372.
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