Full length TECPR1 displays cis Dysferlin domain architecture

Tectonin Beta-Propeller Repeat containing 1 (TECPR1) is an essential regulator of a noncanonical autophagy pathway known as Sphingomyelin TECPR1 induced LC3 lipidation (STIL). TECPR1 forms an E3-like ligase complex and recognizes exposed sphingomyelin on damaged membranes. TECPR1 contains five folded domains however the structural basis for TECPR1 function has remained unresolved. Here, we report the first structure of full length TECPR1 resolved using cryo electron microscopy. TECPR1 forms an elongated hook shaped architecture that positions Dysferlin domains in a cis arrangement. Our structure uncovers an uncharacterized intramolecular interface between tectonin repeat 1 and PH domains. This interaction forms a stabilizing bridge that contributes to the orientation of the DysF domains. Molecular dynamics simulations further demonstrate that TECPR1 maintains the overall structural arrangement during membrane association. Our data provide a structural framework for how TECPR1 domain arrangement corresponds with membrane binding.