SPP 1464:  Principles and Evolution of Actin-nucleator Complexes

• Subject Area: Biology
• Term: from 2010 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 130241892

The actin cytoskeleton is a major determinant of cellular architecture throughout evolution. In parallel with increasing cellular complexity from prokaryotes to metazoans, the diversity of the actin cytoskeleton and its regulators increased. Specific mechanisms evolved to fulfil the novel structural demands of the interactive cellular networks of the animal and plant kingdoms. Despite its fundamental cell biological importance and its enormous implication in human diseases and therapy, many of the underlying regulatory functions have remained elusive for a long time. Only recently, in debt to the impact of the revolutionary gain of knowledge from the genome projects, an increasing number of regulatory mechanisms emerged that reflect the diversity of actin filament structures and functions.
Actin filaments assemble from actin monomers at specified subcellular compartments in response to different signalling cascades. Owing to the fact that the stable association of actin monomers to form dimers and trimers (in a process termed nucleation) is thermodynamically unfavourable, and due to the activity of actin monomer binding proteins, no spontaneous actin polymerisation occurs in cells. Thus, assembly of actin filaments requires factors that help to overcome this kinetic barrier to filament nucleation. Until 2002, the Arp2/3 complex was the only machinery known to drive actin nucleation, but since then, knowledge on the complexity of nucleation mechanisms has exponentially increased, leaving us today with at least 28 different “nucleators” for mammalian cells. These can be divided into three principal groups, i.e. the Arp2/3 complex and its different nucleation promoting factors, formins and WH2-containing nucleators.
The aim of this Priority Programme is to investigate in an interdisciplinary network the structures, the functions, the regulation and the interplay of these nucleators in order to correlate the diversity of nucleation mechanisms with the multitude of distinct cellular actin structures and functions. In addition to cell biological and biochemical assays, including a strong emphasis on structural aspects of the complexes, we expect to obtain invaluable information from a combination of our analysis of actin organisation in a wide range of model organisms (bacteria, fungi, plants, insects, mammals) with bioinformatics approaches. This, together with the design of synthetic actin nucleators as well as biophysical and modelling approaches, should pave the way to a breakthrough in our understanding of the principles and evolution of actin nucleation complexes and will open avenues to translate the results to clinical applications.

• DFG Programme: Priority Programmes
• International Connection: Austria, Spain

Projects

• Actin network architecture in vivo (Applicant Small, John Victor )
• Analysis of WASH and a novel WH2 protein in promoting Arp2/3-mediated actin nucleation in Drosophila (Applicant Bogdan, Sven )
• Biophysics of actin nucleation (Applicant Lamb, Don C. )
• Characterization and membrane targeting of the Spir/formin action nucleator complex (Applicants Kerkhoff, Eugen ;  Schwille, Petra )
• Coordination of the DFG Priority Programme 1464 "Principles and Evolution of Actin Nucleator Complexes" (Applicant Kerkhoff, Eugen )
• Defining the mechanism of actin-mediated spindle position sensing in mouse oocytes (Applicant Ellenberg, Jan )
• Dissection of formin pathways coordinating polarity with cell migration downstream of Ras signalling (Applicant Faix, Jan )
• Evolution of the actin-nucleating machinery (Applicant Kollmar, Martin )
• Formation of neuronal dendrite branches: the role of actin nucleators (Applicant Tavosanis, Gaia )
• Macrophage podosomes as integrative models for formin- and Arp2/3-based actin nucleation (Applicant Linder, Stefan )
• Mechanism, control and cellular functions of Cobl-mediated actin nucleation (Applicant Kessels, Michael Manfred )
• Mechanisms of FHOD1 regulated stress fiber formation (Applicant Nalbant, Ph.D., Perihan )
• Mechanistic Aspects of Actin Polymerization at WH2-proteins: Human Spir and VopF from V. cholerae in Comparison (Applicant Zeth, Kornelius )
• Nucleation and polymerization of MreB, the bacterial otholog of actin (Applicant Graumann, Peter )
• Regulation and cellular functions of the Arp2/3 nucleation complex in actin-driven chromosome transport in oocyte meiosis (Applicant Lénárt, Péter )
• Regulation and function of actin nucleation in the early Drosophila embryo (Applicant Großhans, Jörg )
• Regulation of cellular actin dynamics by FMNL subfamily formins (Applicant Rottner, Klemens )
• Regulation of the WAVE-complex actin nucleation and physiology (Applicant Witke, Walter )
• Relating specific biochemical activities of ADF/cofilin family members to their physiological functions (Applicant Faix, Jan )
• Role of the WAVE-complex in the hematopoietic System (Applicants Sixt, Michael ;  Stradal, Theresia )
• Structure-function analysis of mammalian formins FMNL1 and FMNL2 (Applicant Geyer, Matthias )
• Synthetic control of actin nucleation in vivo (Applicant Wedlich-Söldner, Roland )
• The evolution of actin nucleation - understanding the history of the players (Applicant Schultz, Jörg )
• The role of actin nucleators and nucleation promoting factors in nuclear gene expression via MRTF (Applicant Posern, Guido )
• We will probe the function of two potential formin-like actin nucleation factors in malaria parasite adhesion and motility using recently developed quantitative imaging tools (Applicant Frischknecht, Friedrich )

• Spokesperson: Professor Dr. Eugen Kerkhoff