1Z2M

Crystal Structure of ISG15, the Interferon-Induced Ubiquitin Cross Reactive Protein

Summary for 1Z2M

• Entry DOI: 10.2210/pdb1z2m/pdb
• Related: 1ubq
• Descriptor: interferon, alpha-inducible protein (clone IFI-15K), OSMIUM 4+ ION (3 entities in total)
• Functional Keywords: isg15, ubiquitin cross reactive protein, signaling protein
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P05161
• Total number of polymer chains: 1
• Total formula weight: 17223.76

Authors

Narasimhan, J.,Wang, M.,Fu, Z.,Klein, J.M.,Haas, A.L.,Kim, J.J. (deposition date: 2005-03-08, release date: 2005-05-24, Last modification date: 2024-02-14)

Primary citation

Narasimhan, J.,Wang, M.,Fu, Z.,Klein, J.M.,Haas, A.L.,Kim, J.J.
Crystal Structure of the Interferon-induced Ubiquitin-like Protein ISG15.
J.Biol.Chem., 280:27356-27365, 2005

PubMed Abstract: The biological effects of the ISG15 protein arise in part from its conjugation to cellular targets as a primary response to interferon-alpha/beta induction and other markers of viral or parasitic infection. Recombinant full-length ISG15 has been produced for the first time in high yield by mutating Cys78 to stabilize the protein and by cloning in a C-terminal arginine cap to protect the C terminus against proteolytic inactivation. The cap is subsequently removed with carboxypeptidase B to yield mature biologically active ISG15 capable of stoichiometric ATP-dependent thiolester formation with its human UbE1L activating enzyme. The three-dimensional structure of recombinant ISG15C78S was determined at 2.4-A resolution. The ISG15 structure comprises two beta-grasp folds having main chain root mean square deviation (r.m.s.d.) values from ubiquitin of 1.7 A (N-terminal) and 1.0 A (C-terminal). The beta-grasp domains pack across two conserved 3(10) helices to bury 627 A2 that accounts for 7% of the total solvent-accessible surface area. The distribution of ISG15 surface charge forms a ridge of negative charge extending nearly the full-length of the molecule. Additionally, the N-terminal domain contains an apolar region comprising almost half its solvent accessible surface. The C-terminal domain of ISG15 was superimposed on the structure of Nedd8 (r.m.s.d. = 0.84 A) bound to its AppBp1-Uba3 activating enzyme to model ISG15 binding to UbE1L. The docking model predicts several key side-chain interactions that presumably define the specificity between the ubiquitin and ISG15 ligation pathways to maintain functional integrity of their signaling.

PubMed: 15917233
DOI: 10.1074/jbc.M502814200

Experimental method

X-RAY DIFFRACTION (2.5 Å)