Sequence signals for generation of antigenic peptides by the proteasome: Implications for proteasomal cleavage mechanism
Sequence signals for generation of antigenic peptides by the proteasome: Implications for proteasomal cleavage mechanism
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DOI：
10.1006/jmbi.1999.3392
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发表时间：
2000-01-28
影响因子：
5.6
通讯作者：
Margalit, H
中科院分区：
文献类型：
--
作者：
Altuvia, Y;Margalit, H
蛋白酶体对蛋白质的裂解是大多数提呈给细胞毒性T细胞的抗原肽加工的第一步。然而，其特异性和发病机制尚不完全清楚。为了确定蛋白酶体产生抗原肽的首选序列信号，我们对从MHC I类分子洗脱出来的自然加工多肽的末端和侧翼区域的残基进行了严格的分析。我们的结果表明，C末端(切割位点的位置P1)及其紧邻的侧翼位置(P1‘)都有显著的信号。多肽的N末端仅显示出微弱的这些信号，这与先前的发现一致，即抗原肽可能被具有N末端延伸的蛋白酶体切割。然而，我们成功地间接证明了N-末端裂解位点在P1‘位置包含相同的首选信号。这加强了先前关于切割位点的P1‘位置在决定切割特异性中的作用的研究结果，以及众所周知的位置P1的贡献。我们的结果适用于抗原肽的产生，并对蛋白酶体切割的机制有直接的影响。我们提出了一个蛋白酶体切割机制的模型，根据该模型，被切割片段的两端由相同的切割信号决定，涉及切割位点的P1和P1‘位置上的优先残基。证明了该模型与蛋白质降解产物和抗原肽生成的实验数据的一致性。(C)2000年学术出版社。
Proteasomal cleavage of proteins is the first step in the processing of most antigenic peptides that are presented to cytotoxic T cells. Still, its specificity and mechanism are not fully understood. To identify preferred sequence signals that are used for generation of antigenic peptides by the proteasome, we performed a rigorous analysis of the residues at the termini and flanking regions of naturally processed peptides eluted from MHC class I molecules. Our results show that both the C terminus (position P1 of the cleavage site) and its immediate flanking position (P1') possess significant signals. The N termini of the peptides show these signals only weakly, consistent with previous findings that antigenic peptides may be cleaved by the proteasome with N-terminal extensions. Nevertheless, we succeed to demonstrate indirectly that the N-terminal cleavage sites contain the same preferred signals at position P1'. This reinforces previous findings regarding the role of the P1' position of a cleavage site in determining the cleavage specificity, in addition to the well-known contribution of position P1. Our results apply to the generation of antigenic peptides and bare direct implications for the mechanism of proteasomal cleavage. We propose a model for proteasomal cleavage mechanism by which both ends of cleaved fragments are determined by the same cleavage signals, involving preferred residues at both P1 and P1' positions of a cleavage site. The compatibility of this model with experimental data on protein degradation products and generation of antigenic peptides is demonstrated. (C) 2000 Academic Press.