Characterization of physiological and pathophysiological N-Ank proteins in membrane shaping and cellular morphogenesis

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Cells of multicellular organisms need to adopt specific morphologies. Most cells of multicellular organisms undergo sophisticated shape modulations during development. Neurons show extensive morphology changes during neuronal network formation. However, the molecular mechanisms bringing about membrane topology changes are far from understood – mainly because knowledge of membrane-shaping proteins that can promote local membrane curvatures is still limited. Our analyses recently unveiled that several members of a large, previously unrecognised protein family, which we termed N-Ank proteins, use specific molecular properties to bind and shape membranes. Consistently, functional analyses revealed that the N-Ank protein ankycorbin exemplarily characterized further plays an important role in early morphogenesis of neurons. The here proposed comprehensive characterization of the molecular mechanistic properties of so far only predicted members of the N-Ank family that have been associated with several human diseases and pathophysiologies and of their cellular role in physiology and disease is expected to prove the universality of the N-Ank module on one side and to furthermore define and explain distinct cellular functions of N-Ank proteins. We plan to investigate the importance and the contribution of the following crucial mechanisms i) membrane insertion by an N-terminal amphipathic α-helix, ii) curvature sensing by the curved array of ankyrin repeats and iii) coiled coil-mediated self-association to form nanodomains in the plasma membrane in membrane binding and shaping of wild-type and disease-associated version of distinct N-Ank proteins. Furthermore, we will pursue the exiting working hypothesis of a physical and potentially also functional cooperation of different membrane topology recognizing and modulating proteins, i.e. of N-Ank and F-BAR protein family members in shaping membranes and entire cells. Following analyses of putative cooperation, redundancy and distinct function of these membrane shapers we will investigate their putative functional cooperation in neuromorphogenesis.In summary, we here propose to molecularly characterize physiological and pathophysiological N-Ank proteins, a new class of powerful membrane shapers, and thereby assign mechanistic and cell biological functions to the N-Ank protein superfamily.