Hematopoietic Progenitor Kinase-1 Structure in a Domain-Swapped Dimer

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Antigen-specific T-cell immunity is crucial for treating infectious diseases and cancer.
• Hematopoietic progenitor kinase-1 (HPK1) negatively regulates T-cell receptor signaling, limiting T-cell responses.
• Kinase activity of HPK1 is essential for its function, as shown by catalytic dead mutants.

Purpose of the Study:

• To investigate the structural basis of HPK1 regulation.
• To understand how HPK1's kinase activity influences T-cell function.
• To explore potential therapeutic strategies targeting HPK1.

Main Methods:

• Determined crystal structures of the HPK1 kinase domain (HPK1-KD) in apo and ligand-bound states.
• Evaluated active and inactive HPK1 mutants.
• Utilized biophysical measurements to assess dimer formation in solution.

Main Results:

• HPK1-KD consistently forms a rare domain-swapped dimer in all determined structures.
• The activation segment is integral to the dimer interface and adopts distinct α-helical conformations in active and inactive states.
• Biophysical data confirmed the formation of the HPK1 dimer in solution.

Conclusions:

• The domain-swapped dimer structure of HPK1-KD is a key feature of its regulation.
• Distinct conformations of the activation segment in the dimer suggest altered substrate selectivity.
• Understanding HPK1's dimeric structure provides insights into T-cell signaling and potential therapeutic interventions.