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首页> 外文期刊>Biochemistry >Structural and functional analysis of the pro-domain of human cathelicidin, LL-37
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Structural and functional analysis of the pro-domain of human cathelicidin, LL-37

机译：人cathelicidin LL-37前结构域的结构和功能分析

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摘要

Cathelicidins form a family of small host defense peptides distinct from another class of cationic antimicrobial peptides, the defensins. They are expressed as large precursor molecules with a highly conserved pro-domain known as the cathelin-like domain (CLD). CLDs have high degrees of sequence homology to cathelin, a protein isolated from pig leukocytes and belonging to the cystatin family of cysteine protease inhibitors. In this report, we describe for the first time the X-ray crystal structure of the human CLD (hCLD) of the sole human cathelicidin, LL-37. The structure of the hCLD, determined at 1.93 ? resolution, shows the cystatin-like fold and is highly similar to the structure of the CLD of the pig cathelicidin, protegrin-3. We assayed the in vitro antibacterial activities of the hCLD, LL-37, and the precursor form, pro-cathelicidin (also known as hCAP18), and we found that the unprocessed protein inhibited the growth of Gram-negative bacteria with efficiencies comparable to that of the mature peptide, LL-37. In addition, the antibacterial activity of LL-37 was not inhibited by the hCLD intermolecularly, because exogenously added hCLD had no effect on the bactericidal activity of the mature peptide. The hCLD itself lacked antimicrobial function and did not inhibit the cysteine protease, cathepsin L. Our results contrast with previous reports of hCLD activity. A comparative structural analysis between the hCLD and the cysteine protease inhibitor stefin A showed why the hCLD is unable to function as an inhibitor of cysteine proteases. In this respect, the cystatin scaffold represents an ancestral structural platform from which proteins evolved divergently, with some losing inhibitory functions.
机译：鞘磷脂形成一类小宿主防御肽，与另一类阳离子抗菌肽防御素不同。它们被表达为具有高度保守的前结构域（称为cathelin-like域（CLD））的大型前体分子。 CLD与cathelin具有高度的序列同源性，cathelin是一种从猪白细胞分离的蛋白质，属于半胱氨酸蛋白酶抑制剂的cystatin家族。在本报告中，我们首次描述了唯一的人类cathelicidin LL-37的人类CLD（hCLD）的X射线晶体结构。 hCLD的结构确定为1.93？分辨率，显示出半胱氨酸蛋白酶抑制剂样的折叠，并且与猪cathelicidin，protegrin-3的CLD的结构高度相似。我们分析了hCLD，LL-37和前体形式前cathelicidin（也称为hCAP18）的体外抗菌活性，我们发现未加工的蛋白抑制革兰氏阴性细菌的生长的功效与之相当。成熟肽LL-37。另外，hCLD在分子间没有抑制LL-37的抗菌活性，因为外源添加的hCLD对成熟肽的杀菌活性没有影响。 hCLD本身缺乏抗菌功能，并且不抑制半胱氨酸蛋白酶组织蛋白酶L。我们的结果与以前的hCLD活性报道相反。 hCLD和半胱氨酸蛋白酶抑制剂Stefin A之间的比较结构分析表明，为什么hCLD无法充当半胱氨酸蛋白酶的抑制剂。在这方面，半胱氨酸蛋白酶抑制剂支架代表了祖先的结构平台，蛋白质从该祖先结构平台发散地发展，但失去了某些抑制功能。

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