TY  - INPR
A1  - Preuß, Franziska Friederike
A1  - Chatterjee, Deep
A1  - Mathea, Sebastian
A1  - Shrestha, Safal
A1  - St-Germain, Jonathan
A1  - Saha, Manipa
A1  - Kannan, Natarajan
A1  - Raught, Brian
A1  - Rottapel, Robert
A1  - Knapp, Stefan
T1  - Nucleotide binding, evolutionary insights and interaction partners of the pseudokinase Unc-51-like kinase 4
T2  - bioRxiv
N2  - Unc-51-like kinase 4 (ULK4) is a pseudokinase that has been linked to the development of several diseases. Even though sequence motifs required for ATP binding in kinases are lacking, ULK4 still tightly binds ATP and the presence of the cofactor is required for structural stability of ULK4. Here we present a high-resolution structure of a ULK4-ATPγS complex revealing a highly unusual ATP binding mode in which the lack of the canonical VAIK motif lysine is compensated by K39, located N-terminal to αC. Evolutionary analysis suggests that degradation of active site motifs in metazoan ULK4 has co-occurred with an ULK4 specific activation loop, which stabilizes the C-helix. In addition, cellular interaction studies using BioID and biochemical validation data revealed high confidence interactors of the pseudokinase and armadillo repeat domains. Many of the identified ULK4 interaction partners were centrosomal and tubulin associated proteins and several active kinases suggesting new roles for ULK4.
Highlights: Structure of the ULK4 ATP complex reveals a unique ATP binding mode.
Disease associated mutations modulate ATP binding and ULK4 stability
Degradation of active site motifs co-occurred in evolution with an ULK4 specific activation loop
BioID suggests a role of ULK4 regulating centrosomal and cytoskeletal functions,
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/72773
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-727732
IS  - 2020.06.18.159293
ER  -