Red Cell Cytoskeletal Protein 4.1 During Cell Division

多功能结构蛋白是细胞重塑过程中必不可少的连接体或接头。本提案的长期目标是阐明结构蛋白，特别是细胞骨架蛋白4.1的分子相互作用如何促进细胞分裂。蛋白4.1是一种多功能结构蛋白，在红细胞中整合了对红细胞骨骼组织和机械稳定性调节至关重要的成分。然而，现在已经确定蛋白4.1既在非红系有核细胞中表达，也在红系细胞中表达，并在中心体、有丝分裂纺锤体和细胞核等部位检测到。尽管蛋白4.1在成熟红细胞中的作用已被明确，但其在有核细胞中的作用尚不清楚。我们报道了4.1是微管组织和有丝分裂纺锤体和中心体形成所必需的动力学所必需的。我们还发现至少有两个4.1结构域直接作用于这些亚细胞细胞器的组装。我们的中心假设是，蛋白4.1相互作用连接或整合中心体和纺锤杆内的结构成分，以提供细胞分裂过程中组装/拆卸所需的动态特性。为了详细了解它们之间的相互作用及其机制，我们提出了两个目标：(1)阐明4.1对有丝分裂纺锤体和中心体中微管动力学和组织的调节机制；(2)确定4.1的表达如何影响细胞分裂。我们预计，鉴定蛋白4.1的功能相互作用将进一步增加我们对细胞分裂和分化过程中中心体和有丝分裂纺锤体组装和动力学的基本原理的理解。这反过来可能表明4.1基因缺陷以前未被认识到的病理后果的起源。然而，我们的研究也将为涉及缺陷或缺陷细胞骨架蛋白的分子疾病位点提供广阔的视角。

Multifunctional structural proteins, serving as linkers or adaptors, are essential for cellular remodeling processes. The long-term objective of this proposal is to elucidate how molecular interactions of structural proteins, particularly cytoskeletal protein 4.1, contribute to cell division. Protein 4.1 is a multifunctional structural protein that in red cells integrates components crucial for regulation of red cell skeletal organization and mechanical stability. However, it is now established that protein 4.1 is expressed in non-erythroid nucleated cells as well as in erythroid cells and is detected at sites such as centrosomes, mitotic spindles and nuclei. Although the role of protein 4.1 in mature red cells is well defined, its role(s) in nucleated cells are not well understood. We reported that 4.1 is required for microtubule organization and dynamics essential for proper mitotic spindle and centrosome formation. We also showed that at least two 4.1 domains directly function in assembly of these subcellular organelles. Our central hypothesis is that protein 4.1 interactions link or integrate structural components within centrosomes and spindle poles to provide dynamic properties necessary for assembly/disassembly during cell division. To obtain a detailed understanding of the interactions and mechanisms involved, two Aims are proposed: (1) elucidate mechanisms for 4.1 regulation of microtubule dynamics and organization in mitotic spindle poles and centrosomes, (2) determine how 4.1 expression affects cell division. We anticipate that identifying functional interactions of protein 4.1 will further increase our understanding of fundamental principles of assembly and dynamics of centrosomes and mitotic spindles during cell division and differentiation. This in turn may indicate the genesis of previously unrecognized pathological consequences of 4.1 gene defects. However, our investigations will also contribute a broad perspective on molecular disease loci involving defective or deficient cytoskeletal proteins.