Alpha secretase

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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 ('a disintegrin and metalloprotease domain') 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. [1]

Cleavage of APP via alpha, beta and gamma secretase; defined functions on APP are coloured APP cleavage.png
Cleavage of APP via alpha, beta and gamma secretase; defined functions on APP are coloured

ADAM10 consists of two protein domains, a disintegrin domain and a prodomain; however, only the prodomain is required for APP processing. [2] Other ADAM proteins, ADAM17 (also called TACE, tumor necrosis factor-α converting enzyme), [3] ADAM9, [4] and ADAM19 [5] have also been identified as alpha secretases; extracellular expression of mutant ADAM9 (also known as MDC9 or meltrin gamma) lacking the membrane anchor domain has been suggested as one of many possible means of Alzheimer's prevention and treatment exploiting the alpha secretase pathway. [6] Two distinct modalities of alpha-secretase activity have been observed in cells; constitutive activity occurs mainly at the cell surface[ citation needed ] and is independent of regulatory mechanisms inside the cell, while regulated activity occurs mainly in the golgi and is dependent on the activity of protein kinase C. Alpha-secretase activity in the golgi is thought to compete directly with the beta-secretase pathway for APP substrates during membrane protein maturation. [7] Cell-surface cleavage by alpha secretase is very rapid after APP reaches the cell surface. [8]

The activity of alpha secretases has been implicated in the regulation of learning and memory formation. Release of the APPsα ectodomain has neurotrophic effects that counteract apoptotic signaling and promote synapse formation, processes that are upregulated when ADAM10 is overexpressed. [9] Alpha secretase activity has also been observed to be upregulated in response to the signaling peptide PACAP. [10]

Related alpha-secretases, including ADAM10, have also been implicated in similar maturation events for other transmembrane proteins such as MHC class I proteins. Recent evidence suggests that some such proteins are first processed to ectodomains by alpha secretases and subsequently cleaved by another Alzheimer's-associated protease complex, gamma secretase in its presenilin-complexed form. [11] The Notch pathway bears many similarities to APP processing and is also regulated in part by ADAM10. [12]

Related Research Articles

Beta-secretase 2

Beta-secretase 2 is an enzyme that cleaves Glu-Val-Asn-Leu!Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein. BACE2 is a close homolog of BACE1.

Amyloid beta

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 precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ. 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.

Amyloid-beta precursor protein

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 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.

Amyloid-beta precursor protein secretase

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

Neurodegeneration Central nervous system disease

Neurodegeneration is the progressive loss of structure or function of neurons, which may ultimately involve cell death. Many neurodegenerative diseases—such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, and prion diseases—occur as a result of neurodegenerative processes. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable. Biomedical research has revealed many similarities between these diseases at the sub-cellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

Beta-secretase 1

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.

ADAM (protein)

ADAMs are a family of single-pass transmembrane and secreted metalloendopeptidases. All ADAMs are characterized by a particular domain organization featuring a pro-domain, a metalloprotease, a disintegrin, a cysteine-rich, an epidermal-growth factor like and a transmembrane domain, as well as a C-terminal cytoplasmic tail. Nonetheless, not all human ADAMs have a functional protease domain, which indicates that their biological function mainly depends on protein–protein interactions. Those ADAMs which are active proteases are classified as sheddases because they cut off or shed extracellular portions of transmembrane proteins. For example, ADAM10 can cut off part of the HER2 receptor, thereby activating it. ADAM genes are found in animals, choanoflagellates, fungi and some groups of green algae. Most green algae and all land plants likely lost ADAM proteins.

Gamma secretase

Gamma secretase is a multi-subunit protease complex, itself 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 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, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.

Presenilin

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 at the Centre for Research in Neurodegenerative Diseases at the University of Toronto, and now also at the University of Cambridge. 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.

ADAM17

A disintegrin and metalloprotease 17 (ADAM17), also called TACE, is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases.

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.

Low-density lipoprotein receptor-related protein 8

Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), is a protein that in humans is encoded by the LRP8 gene. ApoER2 is a cell surface receptor that is part of the low-density lipoprotein receptor family. These receptors function in signal transduction and endocytosis of specific ligands. Through interactions with one of its ligands, reelin, ApoER2 plays an important role in embryonic neuronal migration and postnatal long-term potentiation. Another LDL family receptor, VLDLR, also interacts with reelin, and together these two receptors influence brain development and function. Decreased expression of ApoER2 is associated with certain neurological diseases.

PSEN1

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 precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.

ADAM12

Disintegrin and metalloproteinase domain-containing protein 12 is an enzyme that in humans is encoded by the ADAM12 gene. ADAM12 has two splice variants: ADAM12-L, the long form, has a transmembrane region and ADAM12-S, a shorter variant, is soluble and lacks the transmembrane and cytoplasmic domains.

ADAM10

A Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ADAM10 gene.

ADAM9

Disintegrin and metalloproteinase domain-containing protein 9 is an enzyme that in humans is encoded by the ADAM9 gene.

APLP1

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.

ADAM19

ADAM19 , is a human gene.

ADAM28

Disintegrin and metalloproteinase domain-containing protein 28 is an enzyme that in humans is encoded by the ADAM28 gene.

Early-onset Alzheimer's disease, also called early-onset Alzheimer's, younger-onset Alzheimer's or early-onset AD, is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer’s and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's, however, share the same traits as the "late-onset" form and are not caused by genetic mutations. Little is understood about how it starts.

References

  1. ↑ Lammich, S; Kojro, E; Postina, R; Gilbert, S; Pfeiffer, R; Jasionowski, M; Haass, C; Fahrenholz, F (1999). "Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease". Proc Natl Acad Sci USA. 96 (7): 3922–7. doi:10.1073/pnas.96.7.3922. PMC   22396 . PMID   10097139.
  2. ↑ Fahrenholz, F; Gilbert, S; Kojro, E; Lammich, S; Postina, R (2000). "Alpha-secretase activity of the disintegrin metalloprotease ADAM 10. Influences of domain structure". Ann NY Acad Sci. 920: 215–22. doi:10.1111/j.1749-6632.2000.tb06925.x. PMID   11193153.
  3. ↑ Detlev Ganten, Aloys Greither : Molekularmedizinische Grundlagen von altersspezifischen Erkrankungen, 2004, Springer-Verlag, ISBN   3-540-00858-6
  4. ↑ Asai, M; Hattori, C; Szabo, B; Sasagawa, N; Maruyama, K; Tanuma, S; Ishiura, S (2003). "Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase". Biochem Biophys Res Commun. 301 (1): 231–5. doi:10.1016/S0006-291X(02)02999-6. PMID   12535668.
  5. ↑ Tanabe, C; Hotoda, N; Sasagawa, N; Sehara-Fujisawa, A; Maruyama, K; Ishiura, S (2006). "ADAM19 is tightly associated with constitutive Alzheimer's disease APP alpha-secretase in A172 cells". Biochem Biophys Res Commun. 352 (1): 111–7. doi:10.1016/j.bbrc.2006.10.181. PMID   17112471.
  6. ↑ Hotoda, N; Koike, H; Sasagawa, N; Ishiura, S (2002). "A secreted form of human ADAM9 has an alpha-secretase activity for APP". Biochem Biophys Res Commun. 293 (2): 800–5. doi:10.1016/S0006-291X(02)00302-9. PMID   12054541.
  7. ↑ Skovronsky, DM; Moore, DB; Milla, ME; Doms, RW; Lee, VM (2000). "Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network". J Biol Chem. 275 (4): 2568–75. doi: 10.1074/jbc.275.4.2568 . PMID   10644715.
  8. ↑ De Strooper, B; Annaert, W (2000). "Proteolytic processing and cell biological functions of the amyloid precursor protein". J Cell Sci. 113 (11): 1857–70. PMID   10806097.
  9. ↑ Bell, KF; Zheng, L; Fahrenholz, F; Cuello, AC (2006). "ADAM-10 over-expression increases cortical synaptogenesis". Neurobiol Aging. 29 (4): 554–65. doi:10.1016/j.neurobiolaging.2006.11.004. PMID   17187903.
  10. ↑ Kojro, E; Postina, R; Buro, C; Meiringer, C; Gehrig-Burger, K; Fahrenholz, F (2006). "The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein". FASEB J. 20 (3): 512–4. doi:10.1096/fj.05-4812fje. PMID   16401644.
  11. ↑ Carey, BW; Kim, DY; Kovacs, DM (2007). "Presenilin/gamma-secretase and alpha-secretase-like peptidases cleave human MHC Class I proteins". Biochem J. 401 (1): 121–7. doi:10.1042/bj20060847. PMC   1698663 . PMID   17150042.
  12. ↑ Hartmann, D; de Strooper, B; Serneels, L; Craessaerts, K; Herreman, A; Annaert, W; Umans, L; Lubke, T; Lena Illert, A; von Figura, K; Saftig, P (2002). "The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts". Hum Mol Genet. 11 (21): 2615–24. doi: 10.1093/hmg/11.21.2615 . PMID   12354787.
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