2L6L

Solution structure of human J-protein co-chaperone, Dph4

Summary for 2L6L

• Entry DOI: 10.2210/pdb2l6l/pdb
• Descriptor: DnaJ homolog subfamily C member 24, ZINC ION (2 entities in total)
• Functional Keywords: dph4, zn-csl, j-domain, chaperone
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 18051.58

Authors

Thakur, A.,Chitoor, B.S.,Atreya, H.S.,Silva, P.D. (deposition date: 2010-11-23, release date: 2011-12-07, Last modification date: 2024-05-01)

Primary citation

Thakur, A.,Chitoor, B.,Goswami, A.V.,Pareek, G.,Atreya, H.S.,D'Silva, P.
Structure and mechanistic insights into novel iron-mediated moonlighting functions of human J-protein cochaperone, Dph4.
J.Biol.Chem., 287:13194-13205, 2012

PubMed Abstract: J-proteins are obligate cochaperones of Hsp70s and stimulate their ATPase activity via the J-domain. Although the functions of J-proteins have been well understood in the context of Hsp70s, their additional co-evolved "physiological functions" are still elusive. We report here the solution structure and mechanism of novel iron-mediated functional roles of human Dph4, a type III J-protein playing a vital role in diphthamide biosynthesis and normal development. The NMR structure of Dph4 reveals two domains: a conserved J-domain and a CSL-domain connected via a flexible linker-helix. The linker-helix modulates the conformational flexibility between the two domains, regulating thereby the protein function. Dph4 exhibits a unique ability to bind iron in tetrahedral coordination geometry through cysteines of its CSL-domain. The oxidized Fe-Dph4 shows characteristic UV-visible and electron paramagnetic resonance spectral properties similar to rubredoxins. Iron-bound Dph4 (Fe-Dph4) also undergoes oligomerization, thus potentially functioning as a transient "iron storage protein," thereby regulating the intracellular iron homeostasis. Remarkably, Fe-Dph4 exhibits vital redox and electron carrier activity, which is critical for important metabolic reactions, including diphthamide biosynthesis. Further, we observed that Fe-Dph4 is conformationally better poised to perform Hsp70-dependent functions, thus underlining the significance of iron binding in Dph4. Yeast Jjj3, a functional ortholog of human Dph4 also shows a similar iron-binding property, indicating the conserved nature of iron sequestration across species. Taken together, our findings provide invaluable evidence in favor of additional co-evolved specialized functions of J-proteins, previously not well appreciated.

PubMed: 22367199
DOI: 10.1074/jbc.M112.339655

Experimental method

SOLUTION NMR