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首页> 外文期刊>Biochemistry >Increase in Surface Hydrophobicity of the Cataract-Associated P23T Mutant of Human gamma D-Crystallin Is Responsible for Its Dramatically Lower, Retrograde Solubility
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Increase in Surface Hydrophobicity of the Cataract-Associated P23T Mutant of Human gamma D-Crystallin Is Responsible for Its Dramatically Lower, Retrograde Solubility

机译：白内障相关的人类γD-晶体蛋白P23T突变体表面疏水性的增加是其急剧降低的逆行溶解度的原因

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The cataract-associated Pro23 to Thr (P23T) mutation in human gamma D-crystallin (HGD) has a variety of phenotypes and is geographically widespread. Therefore, there is considerable interest in understanding the molecular basis of cataract formation due to this mutation. We showed earlier [Pande, A., et al. (2005) Biochemistry 44, 2491-2500] that the probable basis of opacity in this case is the severely compromised, retrograde solubility and aggregation of P23T relative to HGD. The dramatic solubility change occurs even as the structure of the mutant protein remains essentially unchanged in vitro. We proposed that the retrograde solubility and aggregation of P23T were mediated by net hydrophobic, protein protein interactions. On the basis of these initial findings for P23T and related mutants, and the subsequent finding that they show atypical phase behavior [McManus, J. J., et al. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 16856-16861], we concluded that the protein clusters formed in solutions of the mutant proteins were held together by net hydrophobic, anisotropic interactions. Here we show, using chemical probes, that the surface hydrophobicities of these mutants are inversely related to their solubility. Furthermore, by probing the isolated N-terminal domains of HGD and P23T directly, we find that the increase in the surface hydrophobicity of P23T is localized in the N-terminal domain. Modeling studies suggest the presence of sticky patches on the surface of the N-terminal domain that could be engaged in the formation of protein clusters via hydrophobic protein protein interactions. This work thus provides direct evidence of the dominant role played by net hydrophobic and anisotropic protein protein interactions in the aggregation of P23T.
机译：人γD-晶状体蛋白（HGD）中与白内障相关的Pro23到Thr（P23T）突变具有多种表型，并且在地理上广泛分布。因此，人们非常有兴趣了解由于这种突变而引起的白内障形成的分子基础。我们展示了更早的内容[Pande，A.等。 （2005）Biochemistry 44，2491-2500]，在这种情况下，不透明的可能基础是相对于HGD而言，P23T的严重受损，逆行溶解性和聚集。即使突变蛋白的结构在体外基本保持不变，也会发生巨大的溶解度变化。我们提出，P23T的逆行溶解性和聚集是通过净疏水性，蛋白质-蛋白质相互作用介导的。基于这些对P23T和相关突变体的初步发现，以及随后的发现，它们显示出非典型的相行为[McManus，J. J.，et al。 （2007年）Proc。 Natl。学院科学[U.S.A. 104，16856-16861]，我们得出结论，突变蛋白溶液中形成的蛋白簇通过疏水性，各向异性的净相互作用而结合在一起。在这里，我们显示使用化学探针，这些突变体的表面疏水性与其溶解度成反比。此外，通过直接探测HGD和P23T的分离的N末端结构域，我们发现P23T的表面疏水性增加位于N末端结构域中。建模研究表明，N末端结构域表面上存在粘性斑块，可通过疏水性蛋白质蛋白质相互作用参与蛋白质簇的形成。因此，这项工作提供了直接的证据，证明了净疏水和各向异性蛋白质蛋白质相互作用在P23T聚集中起着主导作用。

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