Dynamin

Dynamin

Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamins are principally involved in the scission of newly formed vesicles from the membrane of one cellular compartment and their targeting to, and fusion with, another compartment, both at the cell surface (particularly caveolae internalization) as well as at the Golgi apparatus. Dynamin also plays a role in many processes including division of organelles, cytokinesis and microbial pathogen resistance.

Introduction of dynamin

Dynamins were originally detected in the brain and identified as microtubule binding partners. It is a 100kD GTPase, which plays a crucial role in clathrin-dependent endocytosis and other vesicular trafficking processes by acting as a pair of molecular scissors for newly formed vesicles originating from the plasma membrane. The dynamin family includes dynamin 1 (DNM1), dynamin 2 (DNM2), and dynamin 3 (DNM3), known as classic dynamins. Although the dynamin isoforms have similar functions, including membrane fission during clathrin-mediated endocytosis, they have different regulatory mechanisms at distinct locations within the cell or while involved in the cellular localization of dynamin. Neurons express high levels of DNM1, while DNM2 is expressed omnipresent. DNM3 is expressed in the brain, testes, and lungs. Each of them consists of five different domains: GTPase domain; middle domain (MD); pleckstrin homology domain (PHD); GTPase effector domain (GED); and proline-rich domain (PRD). Dynamins, other than classic dynamins, are classified into the category of dynamin-like proteins, which lack PHD and PRD, helping in recruiting classic dynamins to split the vesicles. Dynamins and its’ related proteins are significant constituents responsible for the split of clathrin-coated vesicles, mitochondria, and phagosomes. These proteins play an important role in organelle division, viral resistance, and mitochondrial fusion/fission. Dynamin also promotes cell migration and invasion and potentially plays an important role in cell growth, spreading, and neurite outgrowth. Dysfunction and mutations in dynamin have been involved in the pathophysiology of various disorders, such as , osteoporosis, Huntington’s disease, Charcot-Marie-Tooth disease, epilepsy, cancer, dominant optic atrophy, schizophrenia, Down’s syndrome and so on.

Evolution of dynamin inhibitors

The first identified dynamin inhibitors are ammonium salts, such as the dimeric tyrphostins and myristyl trimethyl ammonium bromides (MiTMAB). One important feature of the first generation of dynamin inhibitors is that most of them and their subsequent derivatives inhibit recruitment of dynamin to membranes. However, taking dynasore as an example, compounds that inhibit ATPases and GTPases inhibit the activity of dynamin following recruitment of dynamin to plasma membranes. Surprisingly, dynasore was identified by Macia and his colleagues when they were searching for candidates among 16,000 compounds that were able to inhibit the GTPase activity of dynamin 1. Evidence for the activity of dynasore included inhibition of endocytosis of the transferrin receptor and low density lipoprotein receptor. A characteristic of dynasore is the non-competitive inhibition of the basal and stimulated rates of GTP hydrolysis, without influence on the affinity for GTP binding or dynamin self-assembly. Dynasore treatment on cells inhibits clathrin-mediated endocytosis within 2 minutes, which can be reversed within 20 minutes by removal of the inhibitor. Therefore, the discovery of dynasore offers a valid approach to study endocytosis in a range of cell types derived from different species. Dynasore also has some undesirable properties such as the binding of serum proteins, which brings noneffective dynamin inhibitory activity. Furthermore, dynasore binds to detergents that are constantly used for in vitro drug screening, reducing the potency of the inhibitor. The above-mentioned limitations of dynasore contribute to the synthesis of dihydroxyl and trihydroxyl dynasore analogs with elevated potency and less cytotoxicity and detergent binding.

References:

1. Mahaveer Singh, Hemant R. Jadhav, and Tanya Bhatt. Dynamin Functions and Ligands: Classical Mechanisms Behind. Molecular Pharmacology. 91:123-134.

2. Giulio Preta, James G Cronin and I Martin Sheldon. Dynasore - not just a dynamin inhibitor. Cell Communication and Signaling. 13:13-24.

3. Mark J. Robertson, Gordana Hadzic, Joseph Ambrus, D. Yuri Pomè, Emily Hyde, Ainslie Whiting, Anna Mariana, Lisa von Kleist, Ngoc Chau, Volker Haucke, Phillip J. Robinson, and Adam McCluskey. The Rhodadyns, a New Class of Small Molecule Inhibitors of Dynamin GTPase Activity. ACS Medicinal Chemistry Letters. 3(5):352-356.

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