Anne Straube

A major current focus of my lab is on the cellular function and regulation of molecular motors dynein and KIF1C. We identified KIF1C as a cell polarity regulator and elucidated its cargo-mediated activation mechanism. We found that KIF1C regulates the adhesion of extreme cell protrusions such as the tail of migrating cells by delivering integrins (Theisen et al 2012). Success in purifying functional, full-length recombinant motor proteins enabled significant progress in understanding the regulation and force generation of both KIF1C and dynein. We showed that KIF1C is a highly processive, dimeric motor that is regulated by the intramolecular interaction of its stalk and motor domains. The pseudophosphatase PTPN21 and cargo adapter Hook3 activate KIF1C by binding to the stalk (Siddiqui, Zwetsloot et al 2019). This clearly showed that KIF1C is a dimer autoinhibited by intramolecular interactions rather than undergoing a monomer to dimer transition as shown for other kinesin-3s. In addition, we are beginning to understand how KIF1C responds to force. In contrast to conventional kinesin-1, KIF1C has a higher propensity to slip backwards while remaining attached to the microtubule (Siddiqui at al 2022). We showed that full-length KIF1C can generate forces of several pN and force generation is severely affected by pathogenic mutations in KIF1C that cause hereditary spastic paraplegia. One of our key contributions, is the reconstitution of complexes of KIF1C, dynein, dynactin and hook3, which recapitulate co-dependence of opposite polarity motors for the first time in vitro. KIF1C activates dynein by opening the FHF cargo adapter and extends dynein runs by acting as a processivity factor (Abid Ali, Zwetsloot et al 2025).

Earlier notable contributions from my group are: Together with Andrew McAinsh and Jennifer Ross, we have shown both CLASP1 and uMAP4 prevent excessive dynein-driven astral microtubule movements and thereby ensure proper positioning of the mitotic spindle (Samora, Mogessie et al 2011). We identified a new isoform of MAP4, oMAP4 that organises the paraxial microtubule array in differentiating skeletal muscle cells by forming crosslinks between microtubules that resist motor forces (Mogessie et al 2015). In collaboration with Irina Kaverina, we have shown that CLASPs control both, the trafficking of the kinesin KIF1C (Efimova et al 2014) and the microtubule binding of EB proteins (Grimaldi et al 2014). We have reconstituted the spatially distinct tip tracking of mammalian EB1, EB2 and EB3 and discovered that they recognise the nucleotide state of both tubulins surrounding their binding site (Roth, Fitton et al 2019).