Elongated polyproline motifs facilitate enamel evolution through matrix subunit compaction.
Elongated polyproline motifs facilitate enamel evolution through matrix subunit compaction.
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DOI：
10.1371/journal.pbio.1000262
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发表时间：
2009-12
期刊：
影响因子：
9.8
通讯作者：
Diekwisch TG
中科院分区：
文献类型：
--
作者：
Jin T;Ito Y;Luan X;Dangaria S;Walker C;Allen M;Kulkarni A;Gibson C;Braatz R;Liao X;Diekwisch TG
牙齿和骨骼蛋白质中的Pro-Repeat基序长度如何与脊椎动物的进化有关？与直觉相反的是，较长的重复延伸与超分子基质中较小的聚集亚单位相关，导致哺乳动物与两栖类牙釉质的晶体长度增加。脊椎动物的身体设计依赖于羟基磷灰石作为相对轻的关节内骨骼和复杂的含牙颌骨的主要矿物成分，有助于快速移动和有效捕食。生物矿化和骨骼生长通常是通过含有多聚脯氨酸重复元件的蛋白质来完成的。富含多聚脯氨酸的蛋白质通过其明确的、可移动的和灵活的结构，控制着矿物的形状，并贡献了许多其他生物学功能，包括阿尔茨海默氏症、淀粉样蛋白聚集和醇溶蛋白植物储存。在目前的研究中，我们假设多聚脯氨酸重复蛋白通过改变其中心重复结构域的长度来控制生物事件，如矿物生长、斑块聚集或粘附性，导致超分子组装尺寸的显著变化。为了验证我们的假说，我们以脊椎动物矿化蛋白釉原蛋白为样本，研究了在两栖动物/哺乳动物的转变过程中，多聚脯氨酸串联重复序列长度增加了四倍的生物学效应。为了研究多聚脯氨酸重复长度对基质组装、蛋白质结构和磷灰石晶体生长的影响，我们用原子力显微镜测量了不同脊椎动物的超分子组装尺寸，用电子显微镜测试了蛋白质组装对晶体生长的影响，建立了转基因小鼠模型来研究缩短的多脯氨酸序列对晶体生长的影响，并用三维核磁共振确定了多聚脯氨酸重复元件的结构。我们的研究表明，PXX/PXQ串联重复基序长度的增加导致(1)蛋白质基质亚单位尺寸的紧凑，(2)构象可变性的降低，(3)多聚脯氨酸II螺旋的增加，以及(4)磷灰石晶体长度的增加。综上所述，这些发现建立了多聚脯氨酸串联重复片段组合与脊椎动物矿化组织微结构的进化和设计之间的直接关系。我们的发现表明，在脊索进化的更大背景下，基于多聚脯氨酸的基质组装对磷灰石生长的生物控制为脊椎动物身体计划的进化提供了分子基础。脊椎动物骨骼和牙齿的微结构由富含多聚脯氨酸的蛋白质基质(如釉原蛋白)控制，这些基质充当控制生物磷灰石组装的支架。在牙釉质中，两栖动物有较大的釉原蛋白亚基和较薄的釉质，而哺乳动物的釉质原蛋白亚基较小，伴随着细长的晶体和复杂的棱柱结构。利用在小鼠体内过度表达的特定多肽和青蛙釉原蛋白，我们证实了延长的多聚脯氨酸重复序列的长度对减少基质亚单位尺寸和增加磷灰石晶体长度的影响。核磁共振和表面模拟算法解析的三维结构表明，釉原蛋白中延长的多聚脯氨酸重复伸展通过增加多聚脯氨酸II螺旋影响超分子基质的尺寸，导致超分子亚单位尺寸的紧凑。我们认为，易成形的磷灰石和基于釉原蛋白重复序列的创新机制的可用性对于早期脊椎动物的崛起至关重要，这些生物矿物的区隔和形状使其能够制造出坚固的牙齿和脊椎，这可能使脊椎动物在食物竞争和复杂的运动中具有决定性的生存优势。
How does proline-repeat motif length in the proteins of teeth and bones relate to the evolution of vertebrates? Counterintuitively, longer repeat stretches are associated with smaller aggregated subunits within a supramolecular matrix, resulting in enhanced crystal length in mammalian versus amphibian tooth enamel. Vertebrate body designs rely on hydroxyapatite as the principal mineral component of relatively light-weight, articulated endoskeletons and sophisticated tooth-bearing jaws, facilitating rapid movement and efficient predation. Biological mineralization and skeletal growth are frequently accomplished through proteins containing polyproline repeat elements. Through their well-defined yet mobile and flexible structure polyproline-rich proteins control mineral shape and contribute many other biological functions including Alzheimer's amyloid aggregation and prolamine plant storage. In the present study we have hypothesized that polyproline repeat proteins exert their control over biological events such as mineral growth, plaque aggregation, or viscous adhesion by altering the length of their central repeat domain, resulting in dramatic changes in supramolecular assembly dimensions. In order to test our hypothesis, we have used the vertebrate mineralization protein amelogenin as an exemplar and determined the biological effect of the four-fold increased polyproline tandem repeat length in the amphibian/mammalian transition. To study the effect of polyproline repeat length on matrix assembly, protein structure, and apatite crystal growth, we have measured supramolecular assembly dimensions in various vertebrates using atomic force microscopy, tested the effect of protein assemblies on crystal growth by electron microscopy, generated a transgenic mouse model to examine the effect of an abbreviated polyproline sequence on crystal growth, and determined the structure of polyproline repeat elements using 3D NMR. Our study shows that an increase in PXX/PXQ tandem repeat motif length results (i) in a compaction of protein matrix subunit dimensions, (ii) reduced conformational variability, (iii) an increase in polyproline II helices, and (iv) promotion of apatite crystal length. Together, these findings establish a direct relationship between polyproline tandem repeat fragment assemblies and the evolution and the design of vertebrate mineralized tissue microstructures. Our findings reveal that in the greater context of chordate evolution, the biological control of apatite growth by polyproline-based matrix assemblies provides a molecular basis for the evolution of the vertebrate body plan. The microstructure of vertebrate bones and teeth is controlled by polyproline-rich protein matrices (such as amelogenin) that serve as a scaffold to control the assembly of biological apatites. In tooth enamel, amphibians have large amelogenin subunits and thin enamel while mammals have smaller amelogenin subunits in tandem with elongated crystals and complex prismatic organization. Using specific peptides and frog amelogenin overexpressed in mice, we confirmed the effect of the length of the elongated polyproline repeat on reduced matrix subunit dimensions and enhanced apatite crystal length. Three-dimensional structures solved by NMR (nuclear magnetic resonance) and surface modeling algorithms indicate that elongated polyproline repeat stretches in amelogenins affect the dimensions of the supramolecular matrix through an increase in polyproline II helices, resulting in a compaction of supramolecular subunit dimensions. We propose that the availability of readily shaped apatites and innovative mechanisms based on amelogenin-repeat motifsthat compartmentalize and shape biological minerals was essential for the rise of early vertebrates, enabling the manufacture of strong teeth and backbones that might have given vertebrates a decisive survival advantage in the competition for food and in the sophistication of locomotion.
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