Complex Relationships between Substrate Sequence and Sensitivity to Alterations in 纬-Secretase Processivity Induced by 纬-Secretase Modulators
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- 作者：Joo In Jung ; Yong Ran ; Pedro E. Cruz ; Awilda M. Rosario ; Thomas B. Ladd ; Thomas L. Kukar ; Edward H. Koo ; Kevin M. Felsenstein ; Todd E. Golde
- 刊名：Biochemistry
- 出版年：2014
- 出版时间：April 1, 2014
- 年：2014
- 卷：53
- 期：12
- 页码：1947-1957
- 全文大小：653K
- 年卷期：v.53,no.12(April 1, 2014)
- ISSN：1520-4995
文摘
纬-Secretase catalyzes the final cleavage of the amyloid precursor protein (APP), resulting in the production of amyloid-尾 (A尾) peptides with different carboxyl termini. Presenilin (PSEN) and amyloid precursor protein (APP) mutations linked to early onset familial Alzheimer鈥檚 disease modify the profile of A尾 isoforms generated, by altering both the initial 纬-secretase cleavage site and subsequent processivity in a manner that leads to increased levels of the more amyloidogenic A尾42 and in some circumstances A尾43. Compounds termed 纬-secretase modulators (GSMs) and inverse GSMs (iGSMs) can decrease and increase levels of A尾42, respectively. As GSMs lower the level of production of pathogenic forms of long A尾 isoforms, they are of great interest as potential Alzheimer鈥檚 disease therapeutics. The factors that regulate GSM modulation are not fully understood; however, there is a growing body of evidence that supports the hypothesis that GSM activity is influenced by the amino acid sequence of the 纬-secretase substrate. We have evaluated whether mutations near the luminal border of the transmembrane domain (TMD) of APP alter the ability of both acidic, nonsteroidal anti-inflammatory drug-derived carboxylate and nonacidic, phenylimidazole-derived classes of GSMs and iGSMs to modulate 纬-secretase cleavage. Our data show that point mutations can dramatically reduce the sensitivity to modulation of cleavage by GSMs but have weaker effects on iGSM activity. These studies support the concept that the effect of GSMs may be substrate selective; for APP, it is dependent on the amino acid sequence of the substrate near the junction of the extracellular domain and luminal segment of the TMD.