Molecular mechanistic properties of a novel N-Ank superfamily member, Ankrd24, its functions and its interplay with BAR domain proteins in modulating membranes topologies and shaping cells

• Applicant: Privatdozent Dr. Michael Manfred Kessels
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 500745644

Shaping membranes is crucial for establishing, maintaining and changing the morphology of cellular organelles and of entire cells. Proteins that can directly power the required local membrane topology changes thus attract high interest. Ankyrin repeats adopt a curved structure and are one of the most frequently observed structural features in proteins. We recently proposed that, mainly based on the exemplary examination of ankycorbin, a newly discovered subset of ankyrin repeat proteins, which we termed N-Ank proteins, uses a combination of an amphipathic α-helix and ankyrin repeats to sense membrane curvature and to shape membranes. We here propose to characterize a thus far merely predicted member of this novel superfamily, Ankrd24, as putative membrane shaper, to identify its functions in shaping the dendritic arbor of neurons during their development, to address its molecular and functional interplay with members of the BAR domain protein family of membrane shapers and to unveil the molecular mechanisms Ankrd24 uses for its functions by comprehensive biochemical studies, (ultra-)high-resolution imaging and functional analyses. Detailed characterizations of the molecular mechanistic properties and cell biological functions of Ankrd24 will reveal the fundamental principles Ankrd24 uses to interact with and modulate the topology of membranes. Analyses of Ankrd24 splice variants that affect the N-Ank module will give important insights into the functional consequences of Ankrd24’s alternative splicing in particular and into how to modulate N-Ank module properties in general.Our identification of an interaction of Ankrd24 with another, distinct protein family of membrane shapers furthermore serves as exciting starting point to examine whether and to what extent different membrane topology-recognizing and -modulating proteins cooperate in shaping membranes and entire cells. We will thus address this novel concept by comprehensive biochemical analyses as well as by high-resolution imaging and functional studies in neurons. In summary, studying the mechanisms and the functional role of a putative, novel N-Ank superfamily member in neuromorphogenesis and examining its physical and functional interaction with another membrane shaper of distinct nature will open an important new chapter in our understanding of the morphogenesis of cellular membranes and of entire cells.

• DFG Programme: Research Grants