Foamy Virus Envelope Protein Is a Substrate for Signal Peptide Peptidase-like 3 (SPPL3)*
Foamy Virus Envelope Protein Is a Substrate for Signal Peptide Peptidase-like 3 (SPPL3)*
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DOI：
10.1074/jbc.m112.371369
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发表时间：
2012-11
期刊：
影响因子：
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通讯作者：
M. Voss;Akio Fukumori;Peer-Hendrik Kuhn;U. Künzel;Bärbel Klier;Gudula Grammer;Martina Haug-Kröper;E. Kremmer;S. Lichtenthaler;H. Steiner;B. Schröder;C. Haass;Regina Fluhrer
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作者：
M. Voss;Akio Fukumori;Peer-Hendrik Kuhn;U. Künzel;Bärbel Klier;Gudula Grammer;Martina Haug-Kröper;E. Kremmer;S. Lichtenthaler;H. Steiner;B. Schröder;C. Haass;Regina Fluhrer
背景：SPPL酶是GxGD型的膜内裂解天冬氨酸蛋白酶。结果：在某些情况下，SPPL3不依赖于先前的脱落而切割FVenv，为随后的膜内蛋白降解产生底物。结论：与已知的其他GxGD蛋白水解酶不同，SPPL3在调节的膜内蛋白水解级联反应中可以作为脱水酶和膜内酶。意义：SPPL3的这一初步生化特征将有助于在以后的研究中解决其生理作用。信号肽酶及其同系物、类信号肽酶SPPL2a/b/c和SPPL3，以及γ-分泌酶复合体的催化亚单位早老素，都是GxGD型的膜内裂解天冬氨酸蛋白酶。在这项研究中，我们鉴定了泡沫状病毒包膜蛋白(Fvenv)的18 kDa前导肽(LP18)是人SPPL3和SPPL2a/b进行膜内蛋白分解的新底物。与SPPL2a/b和γ分泌酶不同的是，SPPL2a/b和SPPL2a/b需要胞外结构域小于60个氨基酸的底物才能有效地进行膜内蛋白分解，而SPPL3裂解突变体Fvenv缺乏先前脱落所必需的原蛋白转换酶切割位点。此外，SPPL3产生的FVenv裂解产物为SPPL2a/b连续膜内裂解提供了新的底物。因此，人SPPL3是第一个被证明能够类似于脱落酶的GxGD型天冬氨酸蛋白酶，类似于菱形家族的成员，属于膜内裂解丝氨酸蛋白酶的类别。
Background: SPPL proteases are intramembrane-cleaving aspartyl proteases of the GxGD type. Results: Under certain circumstances, SPPL3 cleaves FVenv independent of prior shedding, generating substrates for subsequent intramembrane proteolysis. Conclusion: Unlike other known GxGD proteases, SPPL3 can act as a sheddase and an intramembrane protease within the regulated intramembrane proteolysis cascade. Significance: This initial biochemical characterization of SPPL3 will help to address its physiological role in later studies. Signal peptide peptidase (SPP), its homologs, the SPP-like proteases SPPL2a/b/c and SPPL3, as well as presenilin, the catalytic subunit of the γ-secretase complex, are intramembrane-cleaving aspartyl proteases of the GxGD type. In this study, we identified the 18-kDa leader peptide (LP18) of the foamy virus envelope protein (FVenv) as a new substrate for intramembrane proteolysis by human SPPL3 and SPPL2a/b. In contrast to SPPL2a/b and γ-secretase, which require substrates with an ectodomain shorter than 60 amino acids for efficient intramembrane proteolysis, SPPL3 cleaves mutant FVenv lacking the proprotein convertase cleavage site necessary for the prior shedding. Moreover, the cleavage product of FVenv generated by SPPL3 serves as a new substrate for consecutive intramembrane cleavage by SPPL2a/b. Thus, human SPPL3 is the first GxGD-type aspartyl protease shown to be capable of acting like a sheddase, similar to members of the rhomboid family, which belong to the class of intramembrane-cleaving serine proteases.