CONSERVATION OF THE SEQUENCE OF ISLET AMYLOID POLYPEPTIDE IN 5 MAMMALS IS CONSISTENT WITH ITS PUTATIVE ROLE AS AN ISLET HORMONE
CONSERVATION OF THE SEQUENCE OF ISLET AMYLOID POLYPEPTIDE IN 5 MAMMALS IS CONSISTENT WITH ITS PUTATIVE ROLE AS AN ISLET HORMONE
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DOI：
10.1073/pnas.86.15.5738
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发表时间：
1989-08-01
影响因子：
11.1
通讯作者：
STEINER, DF
中科院分区：
文献类型：
--
作者：
NISHI, M;CHAN, SJ;STEINER, DF
胰岛淀粉样多肽（IAPP）是在II型（非胰岛素依赖型）糖尿病患者和胰岛素瘤的胰腺淀粉样沉积物中发现的37个氨基酸的肽。我们先前报道了人cDNA的核苷酸序列，这表明IAPP是通过蛋白水解加工89个氨基酸的前体而衍生的C-末端酰胺化肽。我们现在报告的分离的cDNA克隆编码猫，大鼠，小鼠和豚鼠IAPP前体，获得使用“扩增同源DNA片段”（AHF）和“快速扩增cDNA末端”（RACE）的组合。来自这四种哺乳动物的IAPP前体的预测结构显示，每种哺乳动物的IAPP部分通过蛋白水解加工衍生自89至93个氨基酸的前体，并且可能在C末端被酰胺化。这四种哺乳动物的IAPP结构域与人IAPP之间的预测氨基酸序列同一性为89%（猫）、84%（大鼠和小鼠）和78%（豚鼠）。在IAPP结构域内，N-末端和C-末端氨基酸序列在哺乳动物中非常高度保守，结构相关的神经肽降钙素基因相关肽（CGRP）也是如此，这表明IAPP和CGRP与相似但不相同的受体相互作用。相比之下，IAPP前体的N-和C-末端前肽显示出非常少的序列保守性，这表明这些区域不代表另外的生物活性分子。IAPP残基20-29的氨基酸序列的种间变异可能解释了人类和猫胰岛中淀粉样蛋白沉积的存在以及大鼠和小鼠中淀粉样蛋白沉积的缺失。
Islet amyloid polypeptide (IAPP) is a 37-amino acid peptide found in the pancreatic amyloid deposits of type II (non-insulin-dependent) diabetic patients and insulinomas. We previously reported the nucleotide sequence of a human cDNA, which indicated that IAPP is a C-terminally amidated peptide derived by proteolytic processing of an 89-amino acid precursor. We now report the isolation of cDNA clones coding for cat, rat, mouse and guinea pig IAPP precursors, obtained using the combination of "amplification of homologous DNA fragments" (AHF) and "rapid amplification of cDNA ends" (RACE). The predicted structure of IAPP precursors from these four mammals revealed that the IAPP moiety of each is derived from an 89- to 93-amino acid precursor by proteolytic processing and is likely to be amidated at the C terminus. The predicted amino acid sequence identities between the IAPP domains of these four mammals and human IAPP were 89% (cat), 84% (rat and mouse), and 78% (guinea pig). Within the IAPP domains, the N-terminal and C-terminal amino acid sequences are very highly conserved among the mammals, as is also the case with a structurally related neuropeptide, calcitonin-gene-related peptide (CGRP), suggesting that IAPP and CGRP interact with similar though not identical receptors. By contrast, and the N- and C-terminal propeptides of the IAPP precursor show very little sequence conservation, which suggests that these regions do not represent additional biologically active molecules. Interspecies variations in the amino acid sequence of residues 20-29 of IAPP may account for the presence of amyloid deposits in the islets of humans and cats and their absence in rats and mice.