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Substrate recognition and processing by ?-secretase.

ABSTRACT: The ?-secretase complex is composed of four membrane protein subunits, including presenilin as the catalytic component with aspartyl protease activity. The enzyme cleaves within the transmembrane domain of >70 different type I integral membrane proteins and has been dubbed "the proteasome of the membrane". The most studied substrates include the Notch family of receptors, involved in cell differentiation, and the amyloid precursor protein (APP), involved in the pathogenesis of Alzheimer's disease. A central mechanistic question is how ?-secretase recognizes helical transmembrane substrates and carries out processive proteolysis. Recent findings addressing substrate recognition and processing will be discussed, including the role of protease subunit nicastrin as a gatekeeper, the effects of Alzheimer-causing mutations in presenilin on processive proteolysis of APP, and evidence that three pockets in the active site (S1', S2', and S3') determine carboxypeptidase cleavage of substrate in intervals of three residues. This article is part of a Special Issue entitled: Molecular biophysics of membranes and membrane proteins.

SUBMITTER: Wolfe MS

PROVIDER: S-EPMC6899174 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Substrate recognition and processing by γ-secretase.

Wolfe Michael S MS

Biochimica et biophysica acta. Biomembranes 20190708 1

The γ-secretase complex is composed of four membrane protein subunits, including presenilin as the catalytic component with aspartyl protease activity. The enzyme cleaves within the transmembrane domain of >70 different type I integral membrane proteins and has been dubbed "the proteasome of the membrane". The most studied substrates include the Notch family of receptors, involved in cell differentiation, and the amyloid precursor protein (APP), involved in the pathogenesis of Alzheimer's diseas ...[more]

PMID: 31295475

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Project description:The amyloid ?-peptide (A?) of Alzheimer's disease (AD) is generated by proteolysis within the transmembrane domain (TMD) of a C-terminal fragment of the amyloid ? protein-precursor (APP CTF?) by the ?-secretase complex. This processing produces A? ranging from 38 to 49 residues in length. Evidence suggests that this spectrum of A? peptides is the result of successive ?-secretase cleavages, with endoproteolysis first occurring at the ? sites to generate A?48 or A?49, followed by C-terminal trimming mostly every three residues along two product lines to generate shorter, secreted forms of A?: the primary A?49-46-43-40 line and a minor A?48-45-42-38 line. The major secreted A? species are A?40 and A?42, and an increased proportion of the longer, aggregation-prone A?42 compared to A?40 is widely thought to be important in AD pathogenesis. We examined TMD substrate determinants of the specificity and efficiency of ? site endoproteolysis and carboxypeptidase trimming of CTF? by ?-secretase. We determined that the C-terminal negative charge of the intermediate A?49 does not play a role in its trimming by ?-secretase. Peptidomimetic probes suggest that ?-secretase has S1', S2', and S3' pockets, through which trimming by tripeptides may be determined. However, deletion of residues around the ? sites demonstrates that a depth of three residues within the TMD is not a determinant of the location of endoproteolytic ? cleavage of CTF?. We also show that instability of the CTF? TMD helix near the ? site significantly increases endoproteolysis, and that helical instability near the carboxypeptidase cleavage sites facilitates C-terminal trimming by ?-secretase. In addition, we found that CTF? dimers are not endoproteolyzed by ?-secretase. These results support a model in which initial interaction of the array of residues along the undimerized single helical TMD of substrates dictates the site of initial ? cleavage and that helix unwinding is essential for both endoproteolysis and carboxypeptidase trimming.

Dataset Information

Substrate recognition and processing by ?-secretase.

Publications

Substrate recognition and processing by γ-secretase.

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