Procollagen Assembly

这个项目试图揭示胶原蛋白是如何在细胞内组装成形成皮肤、骨骼、软骨和其他组织所需的复杂三维结构的。胶原蛋白是动物生命的分子支架。在胶原生物化学基础知识方面取得的进展将产生可翻译的影响，提高创造设计生物材料的能力，并提高对胶原错误折叠相关遗传疾病的理解。这项研究与一项针对家庭学校社区的成功的科学推广计划的延续和扩展紧密结合在一起。该项目的一个分支涉及麻省理工学院HIP-SAT(Homeschool Internship Program In Science And Technology)，这是一个在全国范围内具有竞争力的项目，将在家上学的学生带到麻省理工学院的领先实验室，进行有资助的暑期研究实习。该计划的第二个环节针对8-14岁的儿童，分发动手操作的分子生物学建模试剂盒，这些试剂盒以支撑生命过程的化学概念吸引学生的注意力，并培训社区有效使用这些试剂盒。纤维状前胶原蛋白由一个长的、不间断的三螺旋结构域组成，两侧是一个小的N-前肽和稍大的球状C-前肽(C-Pro)。三股螺旋本身是成熟胶原蛋白的基本结构元素，是一种三聚体结构，其中三条不同的左旋螺旋相互缠绕，形成右旋平行的三股螺旋。在纤维状胶原中，最丰富的类型，这些三螺旋可以跨越长达1000个氨基酸的长度。这些冗长、重复的三螺旋结构域不能自行正确折叠。相反，他们需要帮助来确保正确的链选择(一些胶原蛋白是同源三聚体，而另一些胶原蛋白形成2：1或甚至1：1：1的杂三聚体)和个别多肽的排列。值得注意的是，胶原蛋白均三聚与异三聚的分子基础尚不清楚。这项研究整合了合成化学、生物化学、结构生物学和细胞生物学的策略，以填补这一关键知识空白。其结果将是理解胶原组装机制的新范式，以及确保适当的胶原组装的热力学和动力学效应之间复杂相互作用的分子解释。这些结果将影响对人类最丰富的蛋白质的基本理解，使生物材料应用成为可能，并阐明与疾病相关的生物学。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This project seeks to uncover how collagen, the molecular scaffold for animal life, assembles inside cells into the complex three-dimensional structures required to form skin, bone, cartilage, and other tissues. The advances in fundamental knowledge of collagen biochemistry achieved will have translatable impact, yielding an enhanced ability to create designer biomaterials and an improved understanding of collagen misfolding-related genetic disorders. The research is tightly integrated with continuation and expansion of a successful science outreach program targeting the homeschool community. One arm of the program involves MIT HIP-SAT (Homeschool Internship Program in Science and Technology), a nationally competitive program that brings homeschooled students to leading labs at MIT for funded summer research internships. A second arm of the program targets children in the 8–14 age range, distributing hands-on molecular biology modeling kits that capture students’ attention with chemical concepts that underpin life processes and training the community in effective use of these kits.The fibrillar procollagens are composed of a lengthy, uninterrupted triple-helical domain flanked by a small N-propeptide and somewhat larger globular C-propeptide (C-Pro). The triple helix itself, which is the fundamental structural element of mature collagen, is a trimeric structure in which three distinct, left-handed helical strands wrap around each other to form the right-handed, parallel triple helix. In fibrillar collagens, the most abundant types, these triple helices can span up to ~1000 amino acids in length. These lengthy, repetitive triple-helical domains cannot fold properly on their own. Instead, they require assistance to ensure proper strand selection (some collagens are homotrimeric, while others form 2:1 or even 1:1:1 heterotrimers) and alignment of individual polypeptides. Remarkably, the molecular basis for collagen homo- versus hetero-trimerization is not yet known. This research integrates strategies from synthetic chemistry, biochemistry, structural biology, and cell biology to fill this key knowledge gap. The outcomes will be a new paradigm for understanding collagen assembly mechanisms, as well as a molecular explanation of the complex interplay between thermodynamic and kinetic effects that ensures proper collagen assembly. These results will impact fundamental understanding of the most abundant protein in humans, enable biomaterial applications, and elucidate disease-relevant biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.