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首页> 外文期刊>Biochemistry >Molecular Mechanism of the Chaperone Function of Mini-alpha-Crystal lin, a 19-Residue Peptide of Human alpha-Crystallin
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Molecular Mechanism of the Chaperone Function of Mini-alpha-Crystal lin, a 19-Residue Peptide of Human alpha-Crystallin

机译：Mini-α-晶林伴蛋白函数的分子机制，人α结晶的19 - 残基肽

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摘要

alpha-Crystallin is the archetypical chaperone of the small heat-shock protein family, all members of which contain the so-called "a-crystallin domain" (ACD). This domain and the N- and C-terminal extensions are considered the main functional units in its chaperone function. Previous studies have shown that a 19-residue fragment of the ACD of human aA-crystallin called mini-aA-crystallin (MAC) shows chaperone properties similar to those of the parent protein. Subsequent studies have confirmed the function of this peptide, but no studies have addressed the mechanistic basis for the chaperone function of MAC. Using human ?D-crystallin (HGD), a key substrate protein for parent a-crystallin in the ocular lens, we show here that MAC not only protects HGD from aggregation during thermal and chemical unfolding but also binds weakly and reversibly to HGD (Kd approximate to 200-700 mu M) even when HGD is in the native state. However, at temperatures favoring the unfolding of HGD, MAC forms a stable complex with HGD similar to parent a-crystallin. Using nuclear magnetic resonance spectroscopy, we identify the residues in HGD that are involved in these two modes of binding and show that MAC protects HGD from aggregation by binding to Phe 56 and Val 132 at the domain interface of the target protein, and residues Val 164 to Leu 167 in the core of the C-terminal domain. Furthermore, we suggest that the low-affinity, reversible binding of MAC on the surface of HGD in the native state is involved in facilitating its binding to both the domain interface and core regions during the early stages of the unfolding of HGD. This work highlights some structural features of MAC and MAC-like peptides that affect their chaperone activity and can potentially be manipulated for translational studies.
机译：α-结晶是小型热休克蛋白家族的原型伴侣，其所有成员含有所谓的“A晶域域”（ACD）。该域和N-和C终端扩展被认为是其伴随其伴随功能的主要功能单元。先前的研究表明，称为Mini-AA结晶（MAC）的人AA-结晶素ACD的19-残基片段显示出与亲本蛋白的伴侣性质。随后的研究证实了该肽的功能，但没有研究已经解决了MAC的伴侣功能的机械基础。使用人αd-晶体（HGD），在眼睛晶状体中的母体A-晶素的关键底物蛋白，我们在此显示MAC不仅可以保护HGD在热和化学展开期间免受聚集的聚集，而且对HGD弱而可逆地结合（KD即使HGD处于原生状态，也要近似为200-700 mu m。然而，在有利于HGD的展开的温度下，MAM与类似于母体A结晶的HGD形成稳定的络合物。使用核磁共振光谱法，我们鉴定了参与这两种结合模式的HGD中的残基，并显示MAC通过在靶蛋白的域界面处与PHE 56和Val 132结合来保护HGD和残留物Val 164在C终端域的核心中到leu 167。此外，我们建议在原生物中的HGD表面上的低亲和力，可逆结合在本地状态下涉及在HGD展开的早期阶段期间与域界面和核心区域的结合促进。这项工作突出了影响其伴随其伴侣活动的MAC和MAC样肽的一些结构特征，并且可能会被操纵用于翻译研究。

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