Title :
structure of macrophage colony stimulating factor bound to
FMS : diverse signaling assemblies of class
III receptor tyrosine kinases
Abstract :
- Macrophage colony stimulating factor ( M-CSF ), through binding to its receptor FMS , a class III receptor tyrosine kinase ( RTK ), regulates the development and function of mononuclear phagocytes, and plays important roles in innate immunity, cancer and inflammation
- We report a 2.4 A crystal structure of M-CSF bound to the first 3 domains (D1-D3) of FMS
- The ligand binding mode of FMS is surprisingly different from KIT , another class III RTK , in which the major ligand-binding domain of FMS , D2, uses the CD and EF loops, but not the beta-sheet on the opposite side of the Ig domain as in KIT , to bind ligand
- Calorimetric data indicate that M-CSF cannot dimerize FMS without receptor- receptor interactions mediated by FMS domains D4 and D5
- Consistently, the structure contains only 1 FMS-D1-D3 molecule bound to a M-CSF dimer , due to a weak, hydrophilic M-CSF : FMS interface, and probably a conformational change of the M-CSF dimer in which binding to the second site is rendered unfavorable by FMS binding at the first site
- The partial, intermediate complex suggests that FMS may be activated in two steps, with the initial engagement step distinct from the subsequent dimerization/activation step
- Hence, the formation of signaling class III RTK complexes can be diverse, engaging various modes of ligand recognition and various mechanistic steps for dimerizing and activating receptors
Output (sent_index, trigger,
protein,
sugar,
site):
Output(Part-Of) (sent_index,
protein,
site):
- 2. FMS, D1-D3
- 2. FMS, domains
- 3. FMS, domain
- 4. FMS, domains
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):