title: Structure-activity relationship of memapsin 2: implications on physiological functions and Alzheimer's disease.
abstract: Memapsin 2 (BACE1, β-secretase), a membrane aspartic protease, functions in the cleavage of the type I transmembrane protein, β-amyloid precursor protein (APP), leading to the production of amyloid β (Aβ) in the brain. Since Aβ is closely associated with the pathogenesis of Alzheimer's disease, understanding the biological function, particularly the catalytic activities of memapsin 2, would assist in a better understanding of the disease and the development of its inhibitors. The transmembrane and cytosolic domains of memapsin 2 function in cellular transport and localization, which are important regulatory mechanisms for its activity. The catalytic ectodomain contains a long substrate cleft that is responsible for substrate recognition, specificity, and peptide bond hydrolysis. The substrate cleft accommodates 11 residues of the substrate in separate binding subsites. Besides APP, a number of membrane proteins have been reported to be substrates of memapsin 2. The elucidation for the specificity of these subsites and the amino acid sequences surrounding the memapsin 2 cleavage site in these proteins has led to the establishment of a predictive model that can quantitatively estimate the efficiency of cleavage for any potential substrates. Such tools may be employed for future studies of memapsin 2 about its biological function. Herein, we review the current knowledge on the structure-function relationship of memapsin 2 and its relationship in the biological function.
authors.affiliation: Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China.
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Hong
authors.forename: Kathleen
authors.initials: K
authors.lastname: Coughlan
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.forename: Jordan
authors.initials: J
authors.lastname: Tang
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020134:Catalytic Domain; D006801:Humans; D021381:Protein Transport; D059748:Proteolysis; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: BACE1; activity prediction; memapsin 2; subsite specificity; β-amyloid