发动蛋白及其蛋白超家族的功能

Functions of Dynamin and Its Family Proteins

发动蛋白(dynamin)作为一种复杂的多结构域蛋白质,因其在促进内吞囊泡形成和断裂,诱导囊泡从质膜脱离过程中发挥重要功能而广为人知。其经典功能是在网格蛋白介导型胞吞作用中发挥“膜剪刀”的作用,但是由于其结构和功能的多样性,不同同源异构体间具有组织表达和分布差异性,促使其广泛参与细胞内重要的生理过程,因此具有重要的研究价值。近期研究揭示了发动蛋白的一些非经典功能,包括参与调控网格蛋白介导型胞吞作用(clathrin-mediated endocytosis,CME)的早期阶段、影响肌动蛋白细胞骨架和细胞分裂等。本文主要综述了发动蛋白在CME膜剪切过程中发挥经典功能的最新进展,总结了其非经典功能的挖掘现状,同时阐述了其他发动蛋白超家族蛋白(dynamin superfamily protein,DSP)成员的功能,如抵抗病原体入侵、参与调控线粒体、过氧化物酶体、液泡膜的分裂,以及线粒体、内质网、液泡、过氧化物酶体膜的融合,此外,DSP成员也在调节细胞器间的物质运输,介导细菌胞质分裂和囊泡分泌等方面发挥功能。本综述通过对DSP成员功能的总结和梳理,将为人类疾病相关的分子机制研究提供思路。

The dynamin superfamily protein(DSP)encompasses a group of large GTPases that are involved in various membrane remodeling processes within the cell.These proteins are characterized by their ability to hydrolyze GTP,which provides the energy necessary for their function in membrane fission,fusion,and tubulation activities.Dynamin superfamily proteins play critical roles in cellular processes such as endocytosis,organelle division,and vesicle trafficking.It is typically classified into classical dynamins and dynamin-related proteins(Drp),which have distinct roles and structural features.Understanding these proteins is crucial for comprehending their functions in cellular processes,particularly in membrane dynamics and organelle maintenance.Classical dynamins are primarily involved in clathrin-mediated endocytosis(CME),a process crucial for the internalization of receptors and other membrane components from the cell surface into the cell.These proteins are best known for their role in pinching off vesicles from the plasma membrane.Structually,classical dynamins are composed of a GTPase domain,a middle domain,a pleckstrin homology(PH)domain that binds phosphoinositides,a GTPase effector domain(GED),and a proline-rich domain(PRD)that interacts with SH3 domain-containing proteins.Functionally,the classical dynamins wrap around the neck of budding vesicles,using GTP hydrolysis to constrict and eventually acting as a“membrane scissor”to cut the vesicle from the membrane.In mammals,there are three major isoforms:dynamin 1(predominantly expressed in neurons),dynamin 2(ubiquitously expressed),and dynamin 3(expressed in testes,lungs,and neurons).Recent studies have also revealed some non-classical functions of classical dynamins,such as regulating the initiation and stabilization of clathrin-coated pits(CCPs)at the early stages of CME,influencing the formation of the actin cytoskeleton and cell division.Drps share structural similarities with classical dynamins but are involved in a variety of different cellular processes,primarily related to the maintenance and remodeling of organelles,and can be mainly categorized into“mediating membrane fission”,“mediating membrane fusion”and“non-membrane-dependent functions”.Proteins like Drp1 are crucial for mitochondrial division,while others like Fis1,Mfn1,and Mfn2 are involved in mitochondrial and peroxisomal fission and fusion processes,which are essential for the maintenance of mitochondrial and peroxisomal integrity and affect energy production and apoptosis.Proteins like the Mx protein family exhibit antiviral properties by interfering with viral replication or assembly,which is critical for the innate immune response to viral infections.Some other proteins are involved in the formation of tubular structures from membranes,which is crucial for the maintenance of organelle morphology,particularly in the endoplasmic reticulum and Golgi apparatus.Studies on dynamin superfamily proteins have been extensive and have significantly advanced our understanding of cellular biology,disease mechanisms,and therapeutic potential.These studies encompass a broad range of disciplines,including molecular biology,biochemistry,cell biology,genetics,and pharmacology.By comprehensively summarizing and organizing the structural features and functions of various members of the dynamin superfamily protein,this review not only deepens the understanding of its molecular mechanisms,but also provides valuable insights for clinical drug research related to human diseases,potentially driving further advancements in the field.