Human health related proteins

The structure of human FK506-binding protein 52 and its implications for the assembly of the glucocorticoid receptor/Hsp90/immunophilin heterocomplex.

The structures of FKBP52 fragments (A) N(1-260) and (B) C(145-459). (C) The putative structure of FKBP52.

FK506-binding protein 52 (FKBP52), which binds FK506 and possesses peptidylprolyl isomerase activity, is an important immunophilin involved in the heterocomplex of steroid receptors with heat-shock protein 90. In 2004, Zihe Rao’s group reported the crystal structures of two overlapping fragments [N(1-260) and C(145-459)] of FKBP52 and the complex with a C-terminal pentapeptide from heat-shock protein 90 (12). Based on the structures of these two overlapping fragments, the complete putative structure of FKBP52 can be defined. The structure of FKBP52 is composed of two consecutive FKBP domains, a tetratricopeptide repeat domain and a short helical domain beyond the final tetratricopeptide repeat motif. Key structural differences between FKBP52 and FKBP51, including the relative orientations of the four domains and some important residue substitutions, could account for the differential functions of FKBPs. This work was published by PNAS (1).


Crystal structure of the ectodomain of human Fc{alpha}RI (CD89)

The crystal structure of the Fc{alpha}RI ectodomain

Human Fc{alpha}RI (CD89) is the specific receptor for IgA, an immunoglobulin that is abundant in mucosa and is also found in high concentrations in serum. Although Fc{alpha}RI is an immunoglobulin Fc receptor (FcR), it differs in many ways from FcRs for other immunoglobulin classes. The genes of most FcRs are located on chromosome 1 at 1q21-23, whereas Fc{alpha}RI is on chromosome 19, at 19q13.4, a region called the leukocyte receptor complex since it is clustered with several leukocyte receptor families including killer cell inhibitory receptors (KIRs) and leukocyte Ig-like receptors (LIRs). The amino acid sequence of Fc{alpha}RI shares only 20% homology with other FcRs but it has around 35% homology with its neighboring LIRs and KIRs. In this work, Zihe Rao and his group analyzed the crystal structure of the ectodomain of Fc{alpha}RI and examined structure similarities between Fc{alpha}RI and KIR2DL1, KIR2DL2 and LIR-1 (2). He showed that Fc{alpha}RI, KIRs, and LIRs share a common hydrophobic core in their interdomain interface, and Fc{alpha}RI is evolutionally closer to LIR than KIR. This work was published as a cover story in J. Biol. Chem. (2).


Crystal structure of human Pirin: an iron-binding nuclear protein and transcription co-factor

The crystal structure of human Pirin

Pirin is a newly identified nuclear protein that interacts with the oncoprotein B-cell lymphoma 3-encoded (Bcl-3) and nuclear factor I (NFI). The crystal structure of human Pirin at 2.1 A resolution, as determined by Zihe Rao’s group, shows it to be a member of the functionally diverse cupin superfamily (3). The structure comprises two beta-barrel domains, with an Fe(II) cofactor bound within the cavity of the N-terminal domain. These findings suggest an enzymatic role for Pirin, most likely in biological redox reactions involving oxygen, and provide compelling evidence that Pirin requires the participation of the metal ion for its interaction with Bcl-3 to co-regulate the NF-kappaB transcription pathway and the interaction with NFI in DNA replication. Substitution of iron by heavy metals thus provides a novel pathway for these metals to directly influence gene transcription. The structure suggests an interesting new role of iron in biology and that Pirin may be involved in novel mechanisms of gene regulation. This work was published in J. Biol. Chem. (3).

References

  1. Wu, B., P. Li, Y. Liu, Z. Lou, Y. Ding, C. Shu, S. Ye, M. Bartlam, B. Shen, and Z. Rao*. 2004. 3D structure of human FK506-binding protein 52: implications for the assembly of the glucocorticoid receptor/Hsp90/immunophilin heterocomplex. Proc Natl Acad Sci U S A 101:8348.
  2. Ding, Y., G. Xu, M. Yang, M. Yao, G. F. Gao, L. Wang, W. Zhang, and Z. Rao*. 2003. Crystal structure of the ectodomain of human FcalphaRI. J Biol Chem 278:27966.
  3. Pang, H., M. Bartlam, Q. Zeng, H. Miyatake, T. Hisano, K. Miki, L. L. Wong, G. F. Gao, and Z. Rao*. 2004. Crystal structure of human pirin: an iron-binding nuclear protein and transcription cofactor. J Biol Chem 279:1491.