Inducers and Inhibitors of AEP. Short peptides such as legumain stabilization and activity modulation (LSAM) domain and αvβ3 integrin could enhance the activity of AEP. LSAM domain known as the prodomain of AEP blocks substrate binding before activation. This prodomain has a helical structure and two independent peptides. One is an activation peptide (AP, K287 to N323), and the other is a LSAM domain. LSAM domain remains even after AP is cleaved and released from protease at neutral pH via electrostatic interaction. AEP without LSAM domain has a lower melting temperature than AEP with LSAM domain [77, 117]. Another short peptide, αvβ3 integrin, can directly interact with AEP, and after forming a complex, the optimal pH for AEP activity is increased from 5.5 to 6.0. It indicates that αvβ3 binding could induce conformational stabilization of AEP accompanied by deprotonated C189. αvβ3 does not directly interact with the AEP active site; however, AEP docks to the αvβ3 RGD-binding site (allosteric effect) [117]. Based on the immunoanalysis, AEP was mostly found in lysosome and endosome as well as cell surface where αvβ3 integrin was localized [118]. Naturally occurred polysaccharides with negative charges, glycosaminoglycans (GAGs), could induce the activity of AEP as well. At low pH, proAEP undergoes autocatalytic activation and this process can be accelerated by some GAGs (such as C4S (chondroitin 4-sulfate), C6S (chondroitin 6-sulfate), C4,6S (chondroitin 4,5- sulfate), heparin, and heparin sulfate) with concentration and time dependencies at pH 4.0 [119–121]. On the other hand, various molecules, both short peptides and chemical agents, have been investigated as potent inhibitors against AEP. AENK (Fmoc-Ala-Glu-Asn-LysNH2) is known to inhibit AEP specifically by blocking the proteolysis of a Dnase inhibitor, SET, both in vitro and in vivo [74, 122]. AENK selectively inhibits AEP’s cleavage activity of α-Syn and tau in a dose-dependent manner [22, 78]. Also, SRPK2, which is abnormally activated in tauopathy in AD, is fragmented by AEP and this proteolytic cleavage is inhibited by AENK as well [85]. In addition, Ac-YVADCHO (acetyl-Tyr-Val-Ala-Asp-aldehyde) could act as an AEP inhibitor as well as a reversible caspase inhibitor. AcESEN-CHO (acetyl-Glu-Ser-Glu-Asn-aldehyde) is also a specific AEP inhibitor. These two short peptides suppressed AEP activity in the plant leaves [123, 124]. Cystatins consist of two groups of cysteine protease inhibitors (type 1 and type 2) that have conserved a sequence as G9, Q53, V55, and G57. Among cystatins, only cystatin C, E/M, and F (belong to type 2) have inhibitory ability against AEP. Cystatin C inhibits AEP almost completely in a dose-dependent manner. Cystatin C, E/M, and F have AEP inhibitory sites that have chemically similar residues in a loop composed of four amino acids (i.e., SNDM, SNSI, and TNDM for cystatin C, E/M, and F, respectively) QUESTION: how does short peptide and/or chemical agents could be a promising strategy to treat AD (Alzheimer disease ) and PD (Parkinson's disease).
Inducers and Inhibitors of AEP.
Short peptides such as legumain stabilization and activity modulation (LSAM) domain and αvβ3 integrin could enhance the activity of AEP. LSAM domain known as the prodomain of AEP blocks substrate binding before activation. This prodomain has a helical structure and two independent peptides. One is an activation peptide (AP, K287 to N323), and the other is a LSAM domain. LSAM domain remains even after AP is cleaved and released from protease at neutral pH via electrostatic interaction. AEP without LSAM domain has a lower melting temperature than AEP with LSAM domain [77, 117]. Another short peptide, αvβ3 integrin, can directly interact with AEP, and after forming a complex, the optimal pH for AEP activity is increased from 5.5 to 6.0. It indicates that αvβ3 binding could induce conformational stabilization of AEP accompanied by deprotonated C189. αvβ3 does not directly interact with the AEP active site; however, AEP docks to the αvβ3 RGD-binding site (allosteric effect) [117]. Based on the immunoanalysis, AEP was mostly found in lysosome and endosome as well as cell surface where αvβ3 integrin was localized [118]. Naturally occurred polysaccharides with negative charges, glycosaminoglycans (GAGs), could induce the activity of AEP as well. At low pH, proAEP undergoes autocatalytic activation and this process can be accelerated by some GAGs (such as C4S (chondroitin 4-sulfate), C6S (chondroitin 6-sulfate), C4,6S (chondroitin 4,5- sulfate), heparin, and heparin sulfate) with concentration and time dependencies at pH 4.0 [119–121]. On the other hand, various molecules, both short peptides and chemical agents, have been investigated as potent inhibitors against AEP. AENK (Fmoc-Ala-Glu-Asn-LysNH2) is known to inhibit AEP specifically by blocking the proteolysis of a Dnase inhibitor, SET, both in vitro and in vivo [74, 122]. AENK selectively inhibits AEP’s cleavage activity of α-Syn and tau in a dose-dependent manner [22, 78]. Also, SRPK2, which is abnormally activated in tauopathy in AD, is fragmented by AEP and this proteolytic cleavage is inhibited by AENK as well [85]. In addition, Ac-YVADCHO (acetyl-Tyr-Val-Ala-Asp-
QUESTION: how does short peptide and/or chemical agents could
be a promising strategy to treat AD (Alzheimer disease ) and PD (Parkinson's disease).
Step by step
Solved in 2 steps
