Border patrol: insights into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and tissue borders.
Border patrol: insights into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and tissue borders.
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DOI：
10.1016/j.matbio.2013.08.004
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发表时间：
2014-02
期刊：
影响因子：
6.9
通讯作者：
Carson, Daniel D.
中科院分区：
文献类型：
--
作者：
Farach-Carson, Mary C.;Warren, Curtis R.;Harrington, Daniel A.;Carson, Daniel D.
关键词：
细胞外基质蛋白聚糖 (ECM) 基底膜蛋白聚糖，也称为硫酸乙酰肝素蛋白聚糖 2 或 HSPG2，是最大 (>200 nm) 和最古老 (>550M 年) 的细胞外基质分子之一。在脊椎动物中，基底膜蛋白的五结构域结构包含许多独立折叠模块，其序列与其他 ECM 蛋白相似，所有这些模块都像汽车一样连接成一个长的、多样化的复杂序列，遵循一个用三个长糖胺聚糖链装饰的独特 N 端结构域 I，以及 C 端结构域 V 中的一个附加糖胺聚糖附着位点。在低等无脊椎动物中，基底膜蛋白通常不是蛋白聚糖，拥有大部分核心蛋白模块，但缺乏结构域 I，糖胺聚糖链的附着位点所在。这表明，在进化后期，为了新的功能目的，将结构域 I 的硫酸乙酰肝素结合生长因子功能与结构域 II-V 中分子其余部分的核心蛋白功能结合起来。在这篇综述中，我们调查了几十年的相关文献，提出了一个基本问题：为什么大自然将这种蛋白质独特地设计为具有单个启动子调节表达的超长多功能蛋白聚糖，而不是将这些功能分离成可以独立调节的单个蛋白质？我们得出的结论是，基底膜聚糖在分隔组织和组织层的功能边界处的浓度是核心蛋白的一个古老的关键功能。在结构域 I 中添加硫酸乙酰肝素链可能是作为将核心蛋白与区域基质和基底膜中的其他 ECM 蛋白结合的额外手段，也是作为在现场储存库中保留生长因子的一种手段，以帮助在受损时快速修复这些边界，例如在受伤期间发生的情况。我们提出了基底膜聚糖的功能，将其作用从我们之前建议的细胞外支架扩展到后生动物复杂组织中建立和巡逻组织边界的关键剂。我们还建议，了解基底膜聚糖分子各个部分的这些独特功能可以为复杂多层组织的工程提供新的见解和工具，包括为建立新组织边界提供必要的线索。
The extracellular matrix proteoglycan (ECM) perlecan, also known as heparan sulfate proteoglycan 2 or HSPG2, is one of the largest (>200 nm) and oldest (>550M years) extracellular matrix molecules. In vertebrates, perlecan’s five-domain structure contains numerous independently folding modules with sequence similarities to other ECM proteins, all connected like cars into one long, diverse complex train following a unique N-terminal domain I decorated with three long glycosaminoglycan chains, and an additional glycosaminoglycan attachment site in the C-terminal domain V. In lower invertebrates, perlecan is not typically a proteoglycan, possessing the majority of the core protein modules, but lacking domain I where the attachment sites for glycosaminoglycan chains are located. This suggests that uniting the heparan sulfate binding growth factor functions of domain I and the core protein functions of the rest of the molecule in domains II-V occurred later in evolution for a new functional purpose. In this review, we surveyed several decades of pertinent literature to ask a fundamental question: Why did nature design this protein uniquely as an extraordinarily long multifunctional proteoglycan with a single promoter regulating expression, rather than separating these functions into individual proteins that could be independently regulated? We arrived at the conclusion that the concentration of perlecan at functional borders separating tissues and tissue layers is an ancient key function of the core protein. The addition of the heparan sulfate chains in domain I likely occurred as an additional means of binding the core protein to other ECM proteins in territorial matrices and basement membranes, and as a means to reserve growth factors in an on-site depot to assist with rapid repair of those borders when compromised, such as would occur during wounding. We propose a function for perlecan that extends its role from that of an extracellular scaffold, as we previously suggested, to that of a critical agent for establishing and patrolling tissue borders in complex tissues in metazoans. We also propose that understanding these unique functions of the individual portions of the perlecan molecule can provide new insights and tools for engineering of complex multi-layered tissues including providing the necessary cues for establishing neotissue borders.
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