Dynamin

Structure

Dynamin itself is a 96 kDa enzyme, and was first isolated when researchers were attempting to isolate new microtubule-based motors from the bovine brain. Dynamin has been extensively studied in the context of clathrin-coated vesicle budding from the cell membrane. Beginning from the N-terminus, Dynamin consists of a GTPase domain connected to a helical stalk domain via a flexible neck region containing a Bundle Signalling Element and GTPase Effector Domain. At the opposite end of the stalk domain is a loop that links to a membrane-binding Pleckstrin homology domain. The protein strand then loops back towards the GTPase domain and terminates with a Proline Rich Domain that binds to the Src Homology domains of many proteins.

Function

During clathrin-mediated endocytosis, the cell membrane invaginates to form a budding vesicle. Dynamin binds to and assembles around the neck of the endocytic vesicle, forming a helical polymer arranged such that the GTPase domains dimerize in an asymmetric manner across helical rungs. The polymer constricts the underlying membrane upon GTP binding and hydrolysis via conformational changes emanating from the flexible neck region that alters the overall helical symmetry. Constriction around the vesicle neck leads to the formation of a hemi-fission membrane state that ultimately results in membrane scission. Constriction may be in part the result of the twisting activity of dynamin, which makes dynamin the only molecular motor known to have a twisting activity.

Types

In mammals, three different dynamin genes have been identified with key sequence differences in their Pleckstrin homology domains leading to differences in the recognition of lipid membranes:

• Dynamin I is expressed in neurons and neuroendocrine cells
• Dynamin II is expressed in most cell types
• Dynamin III is strongly expressed in the testis, but is also present in heart, brain, and lung tissue.

Pharmacology

Small molecule inhibitors of dynamin activity have been developed, including Dynasore and photoswitchable derivatives (Dynazo) for spatiotemporal control of endocytosis with light (photopharmacology).

Disease implications

Mutations in Dynamin II have been found to cause dominant intermediate Charcot-Marie-Tooth disease. Epileptic encephalopathy–causing de novo mutations in dynamin have been suggested to cause dysfunction of vesicle scission during synaptic vesicle endocytosis.

References

References

1. (December 16, 1999). "Participation of dynamin in the biogenesis of cytoplasmic vesicles". The FASEB Journal.
2. Hinshaw, J. [http://www2.niddk.nih.gov/NIDDKLabs/IntramuralFaculty/HinshawJenny.htm "Research statement, Jenny E. Hinshaw, Ph.D."] {{Webarchive. link. (2021-07-15 National Institute of Diabetes & Digestive & Kidney Diseases, Laboratory of Cell Biochemistry and Biology. Accessed 19 March 2013.)
3. (January 1997). "The dynamins: redundant or distinct functions for an expanding family of related GTPases?". Proceedings of the National Academy of Sciences of the United States of America.
4. (October 2005). "Dynamin-related proteins and Pex11 proteins in peroxisome division and proliferation". The FEBS Journal.
5. (March 1995). "Dynamin self-assembles into rings suggesting a mechanism for coated vesicle budding". Nature.
6. (February 2004). "The dynamin superfamily: universal membrane tubulation and fission molecules?". Nature Reviews. Molecular Cell Biology.
7. (August 2014). "A dynamin mutant defines a superconstricted prefission state". Cell Reports.
8. (August 2018). "Cryo-EM of the dynamin polymer assembled on lipid membrane". Nature.
9. (August 2015). "A hemi-fission intermediate links two mechanistically distinct stages of membrane fission". Nature.
10. (May 2006). "GTP-dependent twisting of dynamin implicates constriction and tension in membrane fission". Nature.
11. (June 2006). "Dynasore, a cell-permeable inhibitor of dynamin". Developmental Cell.
12. (November 2018). "Modulation of dynamin function by small molecules". Biological Chemistry.
13. (September 2020). "Correction: Photoswitchable dynasore analogs to control endocytosis with light". Chemical Science.
14. (March 2005). "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease". Nature Genetics.
15. (June 2015). "Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis". Neurology. Genetics.