4.7 Article

The Anti-Inflammatory Protein TNIP1 Is Intrinsically Disordered with Structural Flexibility Contributed by Its AHD1-UBAN Domain

期刊

BIOMOLECULES
卷 10, 期 11, 页码 -

出版社

MDPI
DOI: 10.3390/biom10111531

关键词

intrinsically disordered regions; ABIN-1; linear motifs; NMR; natively unfolded protein

资金

  1. University of Connecticut PATH (Program in Accelerated Therapeutics for Healthcare)
  2. Congressionally Directed Medical Research Programs Discovery grant [W81XWH2010081]
  3. Department of Pharmaceutical Sciences
  4. U.S. Department of Defense (DOD) [W81XWH2010081] Funding Source: U.S. Department of Defense (DOD)

向作者/读者索取更多资源

TNFAIP3 interacting protein 1 (TNIP1) interacts with numerous non-related cellular, viral, and bacterial proteins. TNIP1 is also linked with multiple chronic inflammatory disorders on the gene and protein levels, through numerous single-nucleotide polymorphisms and reduced protein amounts. Despite the importance of TNIP1 function, there is limited investigation as to how its conformation may impact its apparent multiple roles. Hub proteins like TNIP1 are often intrinsically disordered proteins. Our initial in silico assessments suggested TNIP1 is natively unstructured, featuring numerous potentials intrinsically disordered regions, including the ABIN homology domain 1-ubiquitin binding domain in ABIN proteins and NEMO (AHD1-UBAN) domain associated with its anti-inflammatory function. Using multiple biophysical approaches, we demonstrate the structural flexibility of full-length TNIP1 and the AHD1-UBAN domain. We present evidence the AHD1-UBAN domain exists primarily as a pre-molten globule with limited secondary structure in solution. Data presented here suggest the previously described coiled-coil conformation of the crystallized UBAN-only region may represent just one of possibly multiple states for the AHD1-UBAN domain in solution. These data also characterize the AHD1-UBAN domain in solution as mostly monomeric with potential to undergo oligomerization under specific environmental conditions (e.g., binding partner availability, pH-dependence). This proposed intrinsic disorder across TNIP1 and within the AHD1-UBAN region is likely to impact TNIP1 function and interaction with its multiple partners.

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