Journal
BLOOD ADVANCES
Volume 4, Issue 13, Pages 3128-3135Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2020001575
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Funding
- National Heart, Lung, and Blood Institute, National Institutes of Health [HL131654]
- National Natural Science Foundation of China [31370748, 31770967]
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Kindlin-3, a protein 4.1, ezrin, radixin, and moesin (FERM) domain-containing adaptor in hematopoietic cells, is essentially required for supporting the bidirectional integrin ( )alpha IIb beta 3 signaling in platelets by binding to the integrin beta 3 cytoplasmic tail. However, the structural details of kindlin-3's FERM domain remain unknown. In this study, we crystalized the kindlin-3's FERM domain protein and successfully solved its 3-dimensional structure. The structure shows that the 3 kindlin-3's FERM subdomains (F1, F2, and F3) compact together and form a cloverleaf-shaped conformation, which is stabilized by the binding interface between the F1 and F3 subdomains. Interestingly, the FERM domain of kindlin-3 exists as a monomer in both crystal and solution, which is different from its counterpart in kindlin-2 that is able to form a F2 subdomain-swapped dimer nonetheless, dimerization is required for kindlin-3 to support integrin alpha IIb beta 3 activation, indicating that kindlin-3 may use alternative mechanisms for formation of a functional dimer in cells. To evaluate the functional importance of the cloverleaf-like FERM structure in kindlin-3, structure-based mutations were introduced into kindlin-3 to disrupt the F1/F3 interface. The results show that integrin alpha IIb beta 3 activation is significantly suppressed in platelets expressing the kindlin-3 mutant compared with those expressing wild-type kindlin-3. In addition, introduction of equivalent mutations into kindlin-1 and kindlin-2 also significantly compromises their ability to support integrin alpha IIb beta 3 activation in CHO cells. Together, our findings suggest that the cloverleaf-like FERM domain in kindlins is structurally important for supporting integrin alpha IIb beta 3 activation.
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