人眼γD晶状体蛋白致病突变体生物物理化学性质及结构的研究
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摘要
白内障,定义为全部或部分眼睛的晶状体混浊,可分为两大类：先天性和年龄相关性白内障。先天性白内障的患病率估计为每万新生婴儿中2.2-2.5例,其中约50%可遗传。同白内障相关的晶状体蛋白基因突变发生在所有三个晶状体蛋白家族中(α-,β-和γ-晶状体蛋白),并显示为不同的表型。目前,至少有60例遗传性白内障己被记录在案,均由单基因突变引起,相应突变氨基酸也被确定。有些人源γD-晶状体蛋白(HGD)突变体同先天性白内障有着密切联系,但是详细的突变相关性白内障形成的分子机制尚不明确。
基于HGD涉及到蛋白质沉淀疾病,即白内障的形成,本论文以HGD为对象,研究三种HGD的突变体W42R, R76S和P23T的结构,折叠以及组装,探究该晶状体结构与功能之间的关系,进而阐明白内障形成的结构基础。
(1)部分去折叠HGD的中间体,可能使蛋白质聚集沉淀并最终导致晶状体的模糊,人源γD晶状体蛋白突变体同遗传性白内障的形成具有紧密的联系。来源于中国人家庭与白内障相关的γD晶状体蛋白突变体(W42R),表现为常染色体显性遗传,突变体蛋白较HGD溶解性大大下降。我们解析了W42R突变体的晶体结构,分辨率1.7A,同HGD的晶体结构相比较只发现了微小的变化。令人感兴趣的是,W42R突变体蛋白酶水解非常敏感,表明小量部分去折叠成分的存在；核磁共振波谱实验证实并定量分析了部分去折叠成分的存在；氢/氘交换实验也揭示了部分去折叠成分同天然折叠成分之间的化学交换,只是W42R突变体的交换速度及其缓慢。同时,HGD的紫外线辐射实验,导致了蛋白分子N端区域的损伤,辐射后的蛋白对蛋白酶具有同W42R突变体相似的敏感性。所有的实验数据允许我们建立一个基于W42R致病机理的模型,即W42R突变体致病机理可以作为光损伤和年龄相关白内障的代表。
(2)R76S是一个从一个印度家庭新发现的与遗传性白内障相关的HGD突变体,我们在大肠杆菌中表达了该突变体蛋白,通过圆二色,荧光以及NMR确定了蛋白热稳定性和化学稳定性。出乎意料的是,R76S突变体,除了拥有较低的等电点外,在生物物理和生物化学性质方面同HGD并无明显不同,通过NMR确定的R76S突变体的液体结构,包括残余偶极耦合(Resicual Dipoie Couplings, RDCs),弛豫测定,表面其与突变体具有近似相同的液体结构。同时,变性/复性动力学实验表明无论R76S突变体还是野生型突变体都显示了类似的被αB-晶状体蛋白抑制的经由错误折叠途径产生的沉淀。综上所述,研究结果表明结构和稳定性的变化都不是R76S突变体导致白内障产生的原因,但是,等电点的改变和相关表面电位的变化或者氨基酸残基天然性质的变化极有可能影响到R76S突变体与晶状体中其他蛋白家族的相互作用。
(3)与白内障相关的HGD P23T突变体具有地理上广泛分布和表型多样的特性。23位氨基酸残基的突变极大的降低了蛋白质本身的溶解性。由于缺乏P23T突变体的X-ray晶体结构数据,在分子水平上对突变体本身的理解并不充分。本论文工作首次成功解析了P23T突变体的晶体结构,P23T突变体采用P21的结晶群,每个不对称单元包含两个蛋白质分子。同野生型HGD相比,除了一些细微的差别,P23T突变体结构基本保持不变。这些细微差别包括：Trp42的侧链与不同的氨基酸残基形成了新的氢键,结果发生了小角度的转向；同时我们计算P23T突变体和HGD的溶液可接触表面积(SASA),结果并无明显差异。有报道表明P23T突变体溶解度表现为温度退行性(随温度的增加溶解度降低)。在我们的研究中,P23T突变体的溶解度显示出离子强度依赖性,发现在NaCl的存在下P23T突变体的沉淀聚集被部分抑制。综上所述,研究结果表明结构的变化并不是P23T突变体导致白内障产生的原因,但是Thr取代Pro确实改变了蛋白质分子间的相互作用。
综上所述,论文研究表征了W42R突变体的结构特点并揭示了其同年龄相关白内障之间的联系；排除了R76S突变由于自身蛋白-蛋白相互作用导致白内障的可能性；首次解析了P23T突变体的晶体结构。实验数据表明突变带来的HGD主要空间构象上的变化对白内障的发生并不是必要的；但是,突变确实改变了蛋白质分子在溶液中的特性,即不同突变体的变性／复性动力学,在白内障形成中扮演了至关重要的角色。
Cataract, referred to as opacification of all or part of the eye's crystalline lens, can be broadly divided into two classes:early onset (congenital or juvenile) and age-related cataract. The congenital cataracts occur at an estimated prevalence of2.2-2.5cases per10,000live births, and approximately50%of congenital cataracts are inherited. Cataract-associated mutations in the crystallin genes are known to occur in all three crystallin families and show a variety of phenotypes. At the present time, at least60cases of inherited cataracts have been documented; these appear to be caused by a single-gene disorder, and amino acid substitutions have been mapped to the affected genes. Some mutants of human yD-crystallin (HGD) are closely linked to congenital cataracts, although the detailed molecular mechanisms of mutant-associated cataract formation are generally not known.
We focused our studies on HGD and investigated structure-function relationships for this crystallin as it relates to protein deposition diseases, in general, and cataract formation, in particular. We investigated the structure, folding, and assembly of three yD-crystallin mutants including W42R, R76S and P23T mutants. The aim of this work is to elucidate the structural basis for cataract formation.
(i) A recently discovered γD-crystallin mutant (W42R) that has been linked to autosomal dominant, congenital cataracts in a Chinese family. The mutant protein is much less soluble and stable than wild-type γD-crystallin. We solved the crystal structure of W42R at1.7A resolution, which revealed only minor differences from the wild-type structure. Interestingly, the W42R variant is highly susceptible to protease digestion, suggesting the presence of a small population of partially unfolded proteins. This partially unfolded species was confirmed and quantified by NMR spectroscopy. Hydrogen/deuterium exchange experiments revealed chemical exchange between the folded and unfolded species. Exposure of wild-type yD-crystallin to UV caused damage to the N-terminal domain of the protein, resulting in very similar proteolytic susceptibility as observed for the W42R mutant. Altogether, our combined data allowed us to propose a model for W42R pathogenesis, with the W42R mutant serving as a mimic for photodamaged γD-crystallin involved in age-related cataract,
(ⅱ) As part of our ongoing studies on crystallins, we investigated the recently discovered Arg76to Ser (R76S) mutation that is correlated with childhood cataract in an Indian family. We expressed the R76S yD-crystallin protein in E. coli characterized it by CD, fluorescence, and NMR spectroscopy. and determined its stability with respect to thermal and chemical denaturation. Surprisingly, no significant biochemical or biophysical differences were observed between the wild-type protein and the R76S variant, except a lowered pI. NMR assessment of the R76S yD-crystallin solution structure, by RDCs, and of its motional properties, by relaxation measurements, also revealed a close resemblance to wild type crystallin. Further, kinetic unfolding/refolding experiments for R76S and wild-type protein showed similar degrees of off-pathway aggregation suppression by aB-crystallin. Overall, our results suggest that neither structural nor stability changes in the protein are responsible for the R76S yD-crystallin variant's association with cataract. However, the change in pI and the associated surface charge or the altered nature of the amino acid could influence interactions with other lens protein species.
(iii) The cataract-associated P23T mutant is geographically widespread and phenotypically heterogeneous. The mutation at site23of HGD dramatically lowers the solubility of the protein. As yet no X-ray structural data is available for this mutant, atomic level understanding of the mutant protein is not sufficient. Here we firstly and successfully solved the crystal structure of the mutant at2.5A resolution. P23T crystallized in a space group P21with two molecules per asymmetric unit. The structure of the mutant protein remains essentially unchanged when compared to that of HGD except certain minor differences. The side chain of Trp42shifts a small angle by forming new hydrogen bond with the backbone carbonyl group of Ser39. SASA calculations of both wild-type and P23T X-ray structure presents no significant difference as well as the SASA of the exposed hydrophobic residues. P23T was reported exhibiting the retrograde solubility and Pande et al proposed the aggregation of P23T is mediated by net hydrophobic protein-protein interactions. In this research, we observed a ionic strength-dependent solubility of the P23T mutant at room temperature. Overall, our results suggest that no major structural changes in the protein are responsible for the dramatically lower solubility associated with the cataract caused by P23T mutant.
Altogether, our current results and combined previous data clearly show that no major conformational changes of HGD are necessary, as evidenced by the very similar X-ray structures, but that it is solution behavior and in particular (un/folding) dynamics of the different mutants that play critical roles in cataract formation. Indeed, this notion is unambiguously borne out by the results of the study presented here.
基于HGD涉及到蛋白质沉淀疾病,即白内障的形成,本论文以HGD为对象,研究三种HGD的突变体W42R, R76S和P23T的结构,折叠以及组装,探究该晶状体结构与功能之间的关系,进而阐明白内障形成的结构基础。
(1)部分去折叠HGD的中间体,可能使蛋白质聚集沉淀并最终导致晶状体的模糊,人源γD晶状体蛋白突变体同遗传性白内障的形成具有紧密的联系。来源于中国人家庭与白内障相关的γD晶状体蛋白突变体(W42R),表现为常染色体显性遗传,突变体蛋白较HGD溶解性大大下降。我们解析了W42R突变体的晶体结构,分辨率1.7A,同HGD的晶体结构相比较只发现了微小的变化。令人感兴趣的是,W42R突变体蛋白酶水解非常敏感,表明小量部分去折叠成分的存在；核磁共振波谱实验证实并定量分析了部分去折叠成分的存在；氢/氘交换实验也揭示了部分去折叠成分同天然折叠成分之间的化学交换,只是W42R突变体的交换速度及其缓慢。同时,HGD的紫外线辐射实验,导致了蛋白分子N端区域的损伤,辐射后的蛋白对蛋白酶具有同W42R突变体相似的敏感性。所有的实验数据允许我们建立一个基于W42R致病机理的模型,即W42R突变体致病机理可以作为光损伤和年龄相关白内障的代表。
(2)R76S是一个从一个印度家庭新发现的与遗传性白内障相关的HGD突变体,我们在大肠杆菌中表达了该突变体蛋白,通过圆二色,荧光以及NMR确定了蛋白热稳定性和化学稳定性。出乎意料的是,R76S突变体,除了拥有较低的等电点外,在生物物理和生物化学性质方面同HGD并无明显不同,通过NMR确定的R76S突变体的液体结构,包括残余偶极耦合(Resicual Dipoie Couplings, RDCs),弛豫测定,表面其与突变体具有近似相同的液体结构。同时,变性/复性动力学实验表明无论R76S突变体还是野生型突变体都显示了类似的被αB-晶状体蛋白抑制的经由错误折叠途径产生的沉淀。综上所述,研究结果表明结构和稳定性的变化都不是R76S突变体导致白内障产生的原因,但是,等电点的改变和相关表面电位的变化或者氨基酸残基天然性质的变化极有可能影响到R76S突变体与晶状体中其他蛋白家族的相互作用。
(3)与白内障相关的HGD P23T突变体具有地理上广泛分布和表型多样的特性。23位氨基酸残基的突变极大的降低了蛋白质本身的溶解性。由于缺乏P23T突变体的X-ray晶体结构数据,在分子水平上对突变体本身的理解并不充分。本论文工作首次成功解析了P23T突变体的晶体结构,P23T突变体采用P21的结晶群,每个不对称单元包含两个蛋白质分子。同野生型HGD相比,除了一些细微的差别,P23T突变体结构基本保持不变。这些细微差别包括：Trp42的侧链与不同的氨基酸残基形成了新的氢键,结果发生了小角度的转向；同时我们计算P23T突变体和HGD的溶液可接触表面积(SASA),结果并无明显差异。有报道表明P23T突变体溶解度表现为温度退行性(随温度的增加溶解度降低)。在我们的研究中,P23T突变体的溶解度显示出离子强度依赖性,发现在NaCl的存在下P23T突变体的沉淀聚集被部分抑制。综上所述,研究结果表明结构的变化并不是P23T突变体导致白内障产生的原因,但是Thr取代Pro确实改变了蛋白质分子间的相互作用。
综上所述,论文研究表征了W42R突变体的结构特点并揭示了其同年龄相关白内障之间的联系；排除了R76S突变由于自身蛋白-蛋白相互作用导致白内障的可能性；首次解析了P23T突变体的晶体结构。实验数据表明突变带来的HGD主要空间构象上的变化对白内障的发生并不是必要的；但是,突变确实改变了蛋白质分子在溶液中的特性,即不同突变体的变性／复性动力学,在白内障形成中扮演了至关重要的角色。
Cataract, referred to as opacification of all or part of the eye's crystalline lens, can be broadly divided into two classes:early onset (congenital or juvenile) and age-related cataract. The congenital cataracts occur at an estimated prevalence of2.2-2.5cases per10,000live births, and approximately50%of congenital cataracts are inherited. Cataract-associated mutations in the crystallin genes are known to occur in all three crystallin families and show a variety of phenotypes. At the present time, at least60cases of inherited cataracts have been documented; these appear to be caused by a single-gene disorder, and amino acid substitutions have been mapped to the affected genes. Some mutants of human yD-crystallin (HGD) are closely linked to congenital cataracts, although the detailed molecular mechanisms of mutant-associated cataract formation are generally not known.
We focused our studies on HGD and investigated structure-function relationships for this crystallin as it relates to protein deposition diseases, in general, and cataract formation, in particular. We investigated the structure, folding, and assembly of three yD-crystallin mutants including W42R, R76S and P23T mutants. The aim of this work is to elucidate the structural basis for cataract formation.
(i) A recently discovered γD-crystallin mutant (W42R) that has been linked to autosomal dominant, congenital cataracts in a Chinese family. The mutant protein is much less soluble and stable than wild-type γD-crystallin. We solved the crystal structure of W42R at1.7A resolution, which revealed only minor differences from the wild-type structure. Interestingly, the W42R variant is highly susceptible to protease digestion, suggesting the presence of a small population of partially unfolded proteins. This partially unfolded species was confirmed and quantified by NMR spectroscopy. Hydrogen/deuterium exchange experiments revealed chemical exchange between the folded and unfolded species. Exposure of wild-type yD-crystallin to UV caused damage to the N-terminal domain of the protein, resulting in very similar proteolytic susceptibility as observed for the W42R mutant. Altogether, our combined data allowed us to propose a model for W42R pathogenesis, with the W42R mutant serving as a mimic for photodamaged γD-crystallin involved in age-related cataract,
(ⅱ) As part of our ongoing studies on crystallins, we investigated the recently discovered Arg76to Ser (R76S) mutation that is correlated with childhood cataract in an Indian family. We expressed the R76S yD-crystallin protein in E. coli characterized it by CD, fluorescence, and NMR spectroscopy. and determined its stability with respect to thermal and chemical denaturation. Surprisingly, no significant biochemical or biophysical differences were observed between the wild-type protein and the R76S variant, except a lowered pI. NMR assessment of the R76S yD-crystallin solution structure, by RDCs, and of its motional properties, by relaxation measurements, also revealed a close resemblance to wild type crystallin. Further, kinetic unfolding/refolding experiments for R76S and wild-type protein showed similar degrees of off-pathway aggregation suppression by aB-crystallin. Overall, our results suggest that neither structural nor stability changes in the protein are responsible for the R76S yD-crystallin variant's association with cataract. However, the change in pI and the associated surface charge or the altered nature of the amino acid could influence interactions with other lens protein species.
(iii) The cataract-associated P23T mutant is geographically widespread and phenotypically heterogeneous. The mutation at site23of HGD dramatically lowers the solubility of the protein. As yet no X-ray structural data is available for this mutant, atomic level understanding of the mutant protein is not sufficient. Here we firstly and successfully solved the crystal structure of the mutant at2.5A resolution. P23T crystallized in a space group P21with two molecules per asymmetric unit. The structure of the mutant protein remains essentially unchanged when compared to that of HGD except certain minor differences. The side chain of Trp42shifts a small angle by forming new hydrogen bond with the backbone carbonyl group of Ser39. SASA calculations of both wild-type and P23T X-ray structure presents no significant difference as well as the SASA of the exposed hydrophobic residues. P23T was reported exhibiting the retrograde solubility and Pande et al proposed the aggregation of P23T is mediated by net hydrophobic protein-protein interactions. In this research, we observed a ionic strength-dependent solubility of the P23T mutant at room temperature. Overall, our results suggest that no major structural changes in the protein are responsible for the dramatically lower solubility associated with the cataract caused by P23T mutant.
Altogether, our current results and combined previous data clearly show that no major conformational changes of HGD are necessary, as evidenced by the very similar X-ray structures, but that it is solution behavior and in particular (un/folding) dynamics of the different mutants that play critical roles in cataract formation. Indeed, this notion is unambiguously borne out by the results of the study presented here.
引文
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