hCtr1跨膜肽的结构和聚集及模型肽与脂质体相互作用的研究
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摘要
铜离子转运蛋白家族（SLC31）包括铜离子转运蛋白与铜离子转运磷酸化ATP酶（Copper transporting phosphorylated ATPase），其中后者包括ATP7A和ATP7B蛋白。铜离子转运蛋白1（Ctr1）是铜离子的主要摄入蛋白，而ATP7A和ATP7B蛋白主要参与铜离子的转运出胞过程。铜离子转运蛋白家族和细胞内分子伴侣协同调节细胞内外的铜离子的代谢平衡。哺乳动物的铜离子转运蛋白对其胚胎发育至关重要。先天性的铜离子转运蛋白的缺失会导致像Menkes综合症和Wilson等疾病。研究还发现，铜离子转运蛋白家族不仅参与铜离子的转运和代谢，也参与基于铂类的抗肿瘤药物的转运过程。
在酿酒酵母的遗传研究中，在真核细胞的细胞膜上鉴定发现了第一类高亲和力的铜吸收蛋白，yCtr1和yCtr3。Zhou和Gitschier等（1997）在Ctr1缺陷的酵母功能互补的实验中第一次发现人类铜离子摄入基因（hCtr1），该基因位于9q31—q32。后来从hCtr1蛋白的同源序列中分离出了第二个铜离子传输体蛋白hCtr2，它可能与人类细胞内舱隔间释放铜离子有关。研究证实，人类铜离子传输体蛋白1（hCtr1）由190个氨基酸组成，包含有三个假定的跨膜区，一个胞外的N端区域和一个胞内的C端区域。由于缺乏高分辨的原子水平上的三维空间结构，所以对hCtr1蛋白传输铜离子和铂类药物的机理至今还不太清楚。
在本论文中，我们首次运用CD和NMR方法分别研究了hCtr1蛋白三个跨膜肽片段（TMD）在原子水平上的三维空间结构，并尝试用SDS-PAGE和FRET方法对三个跨膜肽片段的聚集进行研究。CD实验结果表明三个跨膜肽片段在40%HFIP/60%H_2O中的结构与在囊泡POPC中的结构相似。NMR实验结果表明，在40%HFIP-d2/60%H_2O中，TMD1在残基Gly67-Glu84之间形成典型的螺旋结构，并且通过C端螺旋紧密堆积形成二聚体；TMD2形成一段较长的螺旋结构，螺旋从残基Leu134到Thr155，形成的螺旋结构具有两亲性，极性残基包括结构上重要的残基如His、Ser、Met等位于同侧，而非极性残基如Leu、Val、Phe等位于另一侧。这样特殊的两亲性结构可能与整个hCtr1蛋白空间结构的形成，以及离子传输过程中离子的选择、转移抑或是调节离子通道的开关有关。螺旋主链上氨基质子的化学位移变化（ΔHN）和分子扩散排序（DOSY）实验表明，TMD2在40%HFIP-d2/60%H_2O中通过疏水残基（Ile141, Ile145, Leu149和Met154）间的相互作用形成三聚体且N端分子间的相互作用较弱，因此三聚体C端（靠近细胞膜外的区域）形成的孔隙尺寸小于N端的尺寸，这一结果与先前通过低温电子显微镜技术报道的结果一致。 TMD3在40%HFIP-d2/60%H_2O中则形成
-helix-coiled segment--helix的特殊结构，螺旋分为两段：Cys161-Gly169和Phe173-Ser176，与残基Gly167构成GXXXG特征基序的残基Gly171不在螺旋中，而是作为一个链接在两段螺旋间。
SDS-PAGE实验表明，三个跨膜肽片段的聚集能力或者形成的聚集体稳定性不同，TMD2﹥TMD1≈TMD3，并且通过此实验还证明TMD2的聚集依赖于溶液中跨膜肽浓度，高浓度下发生聚集。尽管改变在上样缓冲液中的浓度，TMD1和TMD3始终表现为单体形式。在低浓度下的（5.5μМ）FRET实验，也得到了相似的结果，三个跨膜肽在低浓度下都以单体形式存在。蛋白hCtr1的三个跨膜肽片段中，TMD2较强的聚集能力和聚集随浓度变化的特性以及它的两亲性结构，可能在蛋白形成聚集体的过程中起主导因素。
不同的空间三维结构和聚集能力导致三个跨膜肽片段在hCtr1蛋白聚集体的形成和离子传输过程中发挥的生物学功能不同。hCtr1蛋白通过TMD2的聚集诱导和不同亚基间TMD1与TMD3的紧密堆积形成孔隙，且孔隙尺寸的大小很可能受位于孔隙内侧的TMD2取向的调控。由于在TMD2和TMD3之间的loop区较短只有三个残基，因此当TMD2的取向发生变化时必然会引起TMD3的移动，若TMD3整体发生移动则很有可能破坏hCtr1整个蛋白的聚集，但TMD3特殊的
-helix-coiled segment--helix结构，在螺旋间的链接可灵活伸长或缩短，避免了在孔隙尺寸变化时上述情况的发生。但究竟是什么因素诱导TMD2的取向改变，引起孔隙尺寸的大小变化，从而来调控离子通道的开关我们目前还不清楚。
研究已经证实，跨膜肽的疏水长度和膜的疏水厚度之间的疏水性不匹配可能诱导膜蛋白的取向或倾斜角发生变化。在本论文的另一部分中，我们综合运用了荧光光谱、圆二色谱（CD）和衰减全反射傅里叶变换红外光谱（ATR-FTIR）等实验方法，选取了天然抗性相关巨噬细胞蛋白1的第四跨膜区（Nramp1-TMD4）作为模型肽，对其在不同酰基链长的脂质体膜（磷脂酰胆碱-PC、磷脂酰甘油-PG）中,脂质体膜和模型跨膜肽的行为表现进行了研究。研究结果表明，在PG脂质体中TMD4以稳定的螺旋结构形式存在并且螺旋轴平行于脂质体的酰基链。在不同疏水长度的PG中，TMD4的这种结构和取向并不发生变化，而是脂质体的酰基链伸展或弯曲来调整适应TMD4的疏水长度。与在PG中相反，TMD4的螺旋结构在PC中并不稳定。当嵌入不同疏水长度的PC中，TMD4通过改变自身螺旋结构的长短来适应脂质体膜的疏水厚度。除此以外，膜和跨膜肽的这种疏水性不匹配导致嵌入其中的跨膜肽聚集倾向性增加，并且对于同一肽在PC中的聚集倾向性要比在PG中大。
本论文中的研究为揭示hCtr1蛋白传输铜离子和铂类药物的机理提供了结构相关信息，同时疏水性不匹配的研究也为进一步认识膜和跨膜肽的相互作用提供了帮助。
The SLC31family contains two members: copper transporter proteins andcopper transporting phosphorylated ATPases, and the latter includ ATP7A and ATP7Bproteins. At the protein level, two families of membrane proteins control cellularcopper uptake and secretion: copper efflux is governed by the ATP-dependent pumpsATP7A and ATP7B, whereas copper influx is mediated by the copper transporter (Ctr)proteins. The SLC31family and intracellular chaperone co-regulate intracellularmetabolic balance of copper ions. The copper transport protein of mammalian isessential for the embryonic development and the congenital absence will causediseases such as Menkes syndrome and Wilson etc.. Resent studies have confirmedthat the SLC31family not only mediates cellular uptake of copper, but also are linkedto the cellular uptake of Pt-based chemotherapeutic anticancer drugs like cisplatin.
The genes encoding high affinity copper ion transport proteins were firstindentified in the plasma membrane by studies in yeast cells. The human high-affinitycopper transporter (hCtr1) was subsequently isolated by the functionalcomplementation of Ctr1-deficient yeast (Zhou and Gitschier et al.,1997). Thesecond human Ctr family member, hCtr2(SLA31A2), was isolated by sequencehomology to hCtr1, and the function of it may be the release of copper from internalcompartments in human cells. The hCtr1is comprised of190amino acids, includingthree putative transmembrane domains, an extracellular N-terminal region and anintracellular C-terminal region. Because of lacking high-resolution structuralinformation on the atomic level, until now the mechanisms of transporting copper andPt-containing drugs remain obscure.
In our thesis, we firstly used the CD and NMR spectral methods to study thestructure of the three transmembrane domains (TMD) from hCtr1protein, respectively, and try to characterize the aggregation of the three transmembrane domains bySDS-PAGE and FRET methods. The CD results showed that the secondary structuresof the three transmembrane domains in both40%HFIP/60%H_2O and POPC lipidvesicles are similar. We determined the three dimensional structure andoligomerization of the transmembrane domains in40%HFIP/60%H_2O usingsolution-state NMR spectroscopy. And firstly revealed that TMD1forms an-helicalstructure from Gly67to Glu84and is dimerized by close packing of its C-terminalhelix; TMD2forms an amphiphilic-helical structure from Leu134to Thr155and thepolar residues including the residues (His, Ser, Met) that may be important forfunction lie in the same face of the helix, the other face occupied by non-polarresidues (Leu、Val、Phe). The amphiphilic structure may be related to the spatialstructure formation of the hCtr1protein, ion selection and transferring in the processof transporting or regulation of ion channel switch. The chemical shifts of HN protons(HN) in peptides and DOSY experiments demonstrated that the trimerization ofTMD2is induced by the interactions of the apolar residues in the region from thecenter (Ile11) to the C-terminal end (Met24), therefore, the pore size at the C-terminalend of trimer (extracellular end of TMD2in hCtr1) is smaller than that of theN-terminal end. The aggregate result is complied with the previous cryo-EM results.The TMD3adopts a discontinuous helix structure, known as―-helix-coiledsegment--helix‖, and is dimerized by the interaction between the N-terminal parthelices. The motif GxxxG in TMD3is not fully involved in the helix, but partiallyunstructured between helices as a linker.
The SDS-PAGE results suggest that the second transmembrane domain haveintense propensity to aggregate than the first and the third transmembrane domains.The experiments also display that the aggregation of TMD2depends on theconcentration in solution, which is different from the TMD1and TMD3. In the FRETexperiments with lower concentration of peptides (5.5μМ), all the threetransmembrane domains exist as monomer. The intense propensity of aggregation, thedenpendence of aggragation on the concentration and the amphiphilic structure maymake TMD2important in aggregation of hCtr1protein.
Different spatial structure and aggregation ability may have three transmembranedomains different both in trimeric assembly and the role playing in process of iontransporting. The hCTR1forms cone-shaped pore by the packing of TMD2helices inthe inner and by close contact between TMD1and TMD3from different subunit ofhCtr1. The pore size may be regulated by the relative orientation of TMD2heliceslining the inner of the pore, which could induce a cooperative change in theorientation of TMD3helices because the loop between TMD2and TMD3is veryshort (only3residues). The flexible linker between the helices of TMD3accommodates a partial change of the N-terminal half helix in the orientation.However, the detailed mechanism by which the TMDs play roles in the switch of thehCtr1channel is still unknown.
Studies have confirmed that the hydrophobic mismatch between the hydrophobiclength of transmembrane peptide and hydrophobic thickness of lipid membrane mayinduce the changes in membrane protein orientation or tilt angle. In another part ofthis thesis, we combined fluorescence, CD and ATR-IR spectroscopic methods toinvestigate the behaviors of the peptide and lipids under hydrophobic mismatch usinga model peptide from the fourth transmembrane domain of Nramp1, thephosphatidylcholines (PCs) and phosphatidylglycerols (PGs) with different lengths ofacyl chains (14:0,16:0and18:0). The experimental results show that in all PG lipidmembranes, the peptide forms stable-helix structure and the helix axis is parallel tolipid chains. The helical span and orientation are nearly unchanged in varyingthickness of PG membranes, while the lipid chains can deform to accommodate thehydrophobic surface of embedded peptide. In contrast, the helical structures of themodel peptide in PC lipid membranes are less stable. Upon incorporation with PClipid membranes, the peptide can deform itself to accommodate the hydrophobicthickness of lipid membranes in response to hydrophobic mismatch. In addition,hydrophobic mismatch can increase aggregation propensity of the peptide in both PCand PG lipid membranes and the peptide in PC membranes has more aggregationtendency than in PG membranes.
The structural studies of hCtr1-TMDs in our thesis may be meaningful to understand the transporting mechanism of the entire hCtr1protein, and the study onthe hydrophobic mismatching will be helpful to better understanding of the interactionof membrane with transmembrane peptides.
在酿酒酵母的遗传研究中，在真核细胞的细胞膜上鉴定发现了第一类高亲和力的铜吸收蛋白，yCtr1和yCtr3。Zhou和Gitschier等（1997）在Ctr1缺陷的酵母功能互补的实验中第一次发现人类铜离子摄入基因（hCtr1），该基因位于9q31—q32。后来从hCtr1蛋白的同源序列中分离出了第二个铜离子传输体蛋白hCtr2，它可能与人类细胞内舱隔间释放铜离子有关。研究证实，人类铜离子传输体蛋白1（hCtr1）由190个氨基酸组成，包含有三个假定的跨膜区，一个胞外的N端区域和一个胞内的C端区域。由于缺乏高分辨的原子水平上的三维空间结构，所以对hCtr1蛋白传输铜离子和铂类药物的机理至今还不太清楚。
在本论文中，我们首次运用CD和NMR方法分别研究了hCtr1蛋白三个跨膜肽片段（TMD）在原子水平上的三维空间结构，并尝试用SDS-PAGE和FRET方法对三个跨膜肽片段的聚集进行研究。CD实验结果表明三个跨膜肽片段在40%HFIP/60%H_2O中的结构与在囊泡POPC中的结构相似。NMR实验结果表明，在40%HFIP-d2/60%H_2O中，TMD1在残基Gly67-Glu84之间形成典型的螺旋结构，并且通过C端螺旋紧密堆积形成二聚体；TMD2形成一段较长的螺旋结构，螺旋从残基Leu134到Thr155，形成的螺旋结构具有两亲性，极性残基包括结构上重要的残基如His、Ser、Met等位于同侧，而非极性残基如Leu、Val、Phe等位于另一侧。这样特殊的两亲性结构可能与整个hCtr1蛋白空间结构的形成，以及离子传输过程中离子的选择、转移抑或是调节离子通道的开关有关。螺旋主链上氨基质子的化学位移变化（ΔHN）和分子扩散排序（DOSY）实验表明，TMD2在40%HFIP-d2/60%H_2O中通过疏水残基（Ile141, Ile145, Leu149和Met154）间的相互作用形成三聚体且N端分子间的相互作用较弱，因此三聚体C端（靠近细胞膜外的区域）形成的孔隙尺寸小于N端的尺寸，这一结果与先前通过低温电子显微镜技术报道的结果一致。 TMD3在40%HFIP-d2/60%H_2O中则形成
-helix-coiled segment--helix的特殊结构，螺旋分为两段：Cys161-Gly169和Phe173-Ser176，与残基Gly167构成GXXXG特征基序的残基Gly171不在螺旋中，而是作为一个链接在两段螺旋间。
SDS-PAGE实验表明，三个跨膜肽片段的聚集能力或者形成的聚集体稳定性不同，TMD2﹥TMD1≈TMD3，并且通过此实验还证明TMD2的聚集依赖于溶液中跨膜肽浓度，高浓度下发生聚集。尽管改变在上样缓冲液中的浓度，TMD1和TMD3始终表现为单体形式。在低浓度下的（5.5μМ）FRET实验，也得到了相似的结果，三个跨膜肽在低浓度下都以单体形式存在。蛋白hCtr1的三个跨膜肽片段中，TMD2较强的聚集能力和聚集随浓度变化的特性以及它的两亲性结构，可能在蛋白形成聚集体的过程中起主导因素。
不同的空间三维结构和聚集能力导致三个跨膜肽片段在hCtr1蛋白聚集体的形成和离子传输过程中发挥的生物学功能不同。hCtr1蛋白通过TMD2的聚集诱导和不同亚基间TMD1与TMD3的紧密堆积形成孔隙，且孔隙尺寸的大小很可能受位于孔隙内侧的TMD2取向的调控。由于在TMD2和TMD3之间的loop区较短只有三个残基，因此当TMD2的取向发生变化时必然会引起TMD3的移动，若TMD3整体发生移动则很有可能破坏hCtr1整个蛋白的聚集，但TMD3特殊的
-helix-coiled segment--helix结构，在螺旋间的链接可灵活伸长或缩短，避免了在孔隙尺寸变化时上述情况的发生。但究竟是什么因素诱导TMD2的取向改变，引起孔隙尺寸的大小变化，从而来调控离子通道的开关我们目前还不清楚。
研究已经证实，跨膜肽的疏水长度和膜的疏水厚度之间的疏水性不匹配可能诱导膜蛋白的取向或倾斜角发生变化。在本论文的另一部分中，我们综合运用了荧光光谱、圆二色谱（CD）和衰减全反射傅里叶变换红外光谱（ATR-FTIR）等实验方法，选取了天然抗性相关巨噬细胞蛋白1的第四跨膜区（Nramp1-TMD4）作为模型肽，对其在不同酰基链长的脂质体膜（磷脂酰胆碱-PC、磷脂酰甘油-PG）中,脂质体膜和模型跨膜肽的行为表现进行了研究。研究结果表明，在PG脂质体中TMD4以稳定的螺旋结构形式存在并且螺旋轴平行于脂质体的酰基链。在不同疏水长度的PG中，TMD4的这种结构和取向并不发生变化，而是脂质体的酰基链伸展或弯曲来调整适应TMD4的疏水长度。与在PG中相反，TMD4的螺旋结构在PC中并不稳定。当嵌入不同疏水长度的PC中，TMD4通过改变自身螺旋结构的长短来适应脂质体膜的疏水厚度。除此以外，膜和跨膜肽的这种疏水性不匹配导致嵌入其中的跨膜肽聚集倾向性增加，并且对于同一肽在PC中的聚集倾向性要比在PG中大。
本论文中的研究为揭示hCtr1蛋白传输铜离子和铂类药物的机理提供了结构相关信息，同时疏水性不匹配的研究也为进一步认识膜和跨膜肽的相互作用提供了帮助。
The SLC31family contains two members: copper transporter proteins andcopper transporting phosphorylated ATPases, and the latter includ ATP7A and ATP7Bproteins. At the protein level, two families of membrane proteins control cellularcopper uptake and secretion: copper efflux is governed by the ATP-dependent pumpsATP7A and ATP7B, whereas copper influx is mediated by the copper transporter (Ctr)proteins. The SLC31family and intracellular chaperone co-regulate intracellularmetabolic balance of copper ions. The copper transport protein of mammalian isessential for the embryonic development and the congenital absence will causediseases such as Menkes syndrome and Wilson etc.. Resent studies have confirmedthat the SLC31family not only mediates cellular uptake of copper, but also are linkedto the cellular uptake of Pt-based chemotherapeutic anticancer drugs like cisplatin.
The genes encoding high affinity copper ion transport proteins were firstindentified in the plasma membrane by studies in yeast cells. The human high-affinitycopper transporter (hCtr1) was subsequently isolated by the functionalcomplementation of Ctr1-deficient yeast (Zhou and Gitschier et al.,1997). Thesecond human Ctr family member, hCtr2(SLA31A2), was isolated by sequencehomology to hCtr1, and the function of it may be the release of copper from internalcompartments in human cells. The hCtr1is comprised of190amino acids, includingthree putative transmembrane domains, an extracellular N-terminal region and anintracellular C-terminal region. Because of lacking high-resolution structuralinformation on the atomic level, until now the mechanisms of transporting copper andPt-containing drugs remain obscure.
In our thesis, we firstly used the CD and NMR spectral methods to study thestructure of the three transmembrane domains (TMD) from hCtr1protein, respectively, and try to characterize the aggregation of the three transmembrane domains bySDS-PAGE and FRET methods. The CD results showed that the secondary structuresof the three transmembrane domains in both40%HFIP/60%H_2O and POPC lipidvesicles are similar. We determined the three dimensional structure andoligomerization of the transmembrane domains in40%HFIP/60%H_2O usingsolution-state NMR spectroscopy. And firstly revealed that TMD1forms an-helicalstructure from Gly67to Glu84and is dimerized by close packing of its C-terminalhelix; TMD2forms an amphiphilic-helical structure from Leu134to Thr155and thepolar residues including the residues (His, Ser, Met) that may be important forfunction lie in the same face of the helix, the other face occupied by non-polarresidues (Leu、Val、Phe). The amphiphilic structure may be related to the spatialstructure formation of the hCtr1protein, ion selection and transferring in the processof transporting or regulation of ion channel switch. The chemical shifts of HN protons(HN) in peptides and DOSY experiments demonstrated that the trimerization ofTMD2is induced by the interactions of the apolar residues in the region from thecenter (Ile11) to the C-terminal end (Met24), therefore, the pore size at the C-terminalend of trimer (extracellular end of TMD2in hCtr1) is smaller than that of theN-terminal end. The aggregate result is complied with the previous cryo-EM results.The TMD3adopts a discontinuous helix structure, known as―-helix-coiledsegment--helix‖, and is dimerized by the interaction between the N-terminal parthelices. The motif GxxxG in TMD3is not fully involved in the helix, but partiallyunstructured between helices as a linker.
The SDS-PAGE results suggest that the second transmembrane domain haveintense propensity to aggregate than the first and the third transmembrane domains.The experiments also display that the aggregation of TMD2depends on theconcentration in solution, which is different from the TMD1and TMD3. In the FRETexperiments with lower concentration of peptides (5.5μМ), all the threetransmembrane domains exist as monomer. The intense propensity of aggregation, thedenpendence of aggragation on the concentration and the amphiphilic structure maymake TMD2important in aggregation of hCtr1protein.
Different spatial structure and aggregation ability may have three transmembranedomains different both in trimeric assembly and the role playing in process of iontransporting. The hCTR1forms cone-shaped pore by the packing of TMD2helices inthe inner and by close contact between TMD1and TMD3from different subunit ofhCtr1. The pore size may be regulated by the relative orientation of TMD2heliceslining the inner of the pore, which could induce a cooperative change in theorientation of TMD3helices because the loop between TMD2and TMD3is veryshort (only3residues). The flexible linker between the helices of TMD3accommodates a partial change of the N-terminal half helix in the orientation.However, the detailed mechanism by which the TMDs play roles in the switch of thehCtr1channel is still unknown.
Studies have confirmed that the hydrophobic mismatch between the hydrophobiclength of transmembrane peptide and hydrophobic thickness of lipid membrane mayinduce the changes in membrane protein orientation or tilt angle. In another part ofthis thesis, we combined fluorescence, CD and ATR-IR spectroscopic methods toinvestigate the behaviors of the peptide and lipids under hydrophobic mismatch usinga model peptide from the fourth transmembrane domain of Nramp1, thephosphatidylcholines (PCs) and phosphatidylglycerols (PGs) with different lengths ofacyl chains (14:0,16:0and18:0). The experimental results show that in all PG lipidmembranes, the peptide forms stable-helix structure and the helix axis is parallel tolipid chains. The helical span and orientation are nearly unchanged in varyingthickness of PG membranes, while the lipid chains can deform to accommodate thehydrophobic surface of embedded peptide. In contrast, the helical structures of themodel peptide in PC lipid membranes are less stable. Upon incorporation with PClipid membranes, the peptide can deform itself to accommodate the hydrophobicthickness of lipid membranes in response to hydrophobic mismatch. In addition,hydrophobic mismatch can increase aggregation propensity of the peptide in both PCand PG lipid membranes and the peptide in PC membranes has more aggregationtendency than in PG membranes.
The structural studies of hCtr1-TMDs in our thesis may be meaningful to understand the transporting mechanism of the entire hCtr1protein, and the study onthe hydrophobic mismatching will be helpful to better understanding of the interactionof membrane with transmembrane peptides.
引文
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