TXNL4B

TXNL4B (DLP/hDim2) is a nuclear thioredoxin-fold protein that functions as a spliceosome-associated factor governing pre-mRNA splicing and cell cycle progression (PMID:15161931). It adopts a classical thioredoxin fold elaborated by an extra α3 helix and β5 strand and, unlike its paralog hDim1, assembles into stable homodimers stabilized by electrostatic interactions involving tyrosine residues in the α3 helix; it lacks the structural motifs required for hDim1 activity, indicating that the two proteins act in distinct multisubunit complexes (PMID:16142897). TXNL4B engages the spliceosome through interaction with the U5-102-kDa subunit, and its loss results in insufficient pre-mRNA splicing and failure of the S/G2 cell cycle transition (PMID:15161931). Following ionizing radiation, TXNL4B interacts and co-localizes in the nucleus with the splicing factor PRP3, which drives alternative splicing of FANCI pre-mRNA; depletion of TXNL4B increases radiosensitivity, causes G2/M arrest, and delays DNA damage repair (PMID:37168687).

1. 2004 Medium

   Established TXNL4B as a nuclear spliceosome-associated protein by linking it physically to the splicing machinery and functionally to RNA processing and cell division.

   Evidence Molecular cloning with subcellular localization, interaction assays against the U5-102-kDa subunit, and knockdown with splicing and cell cycle readouts

   PMID:15161931

   Open questions at the time

   • No structural basis for the U5-102-kDa interaction
   • Direct splicing substrates not identified
   • Mechanism linking splicing role to S/G2 transition unresolved
2. 2005 High

   Defined the molecular architecture that distinguishes TXNL4B from its paralog, showing it is a homodimeric thioredoxin-fold protein lacking hDim1 activity motifs and thus likely acting in a different complex.

   Evidence X-ray crystallography at 2.5 Å with CD, fluorescence, size-exclusion chromatography and cross-linking; complemented by a high-quality recombinant crystallization report

   PMID:16142897 PMID:16511018

   Open questions at the time

   • Functional consequence of homodimerization in splicing not tested
   • hDim2-specific partner predicted from α3/β5 elements not identified
3. 2013 High

   Refined the structure to near-atomic resolution and reinterpreted the proposed Prp6-binding region, showing residues 1–33 are buried in the fold core rather than freely available for interaction.

   Evidence X-ray crystallography at 1.33 Å resolution with structural mapping of the previously assigned interaction region

   PMID:23519793

   Open questions at the time

   • Does not define the true Prp6 interaction surface
   • No co-complex structure with any spliceosomal partner
4. 2023 Medium

   Connected TXNL4B to the DNA damage response by tying its splicing function, via PRP3, to alternative splicing of FANCI and to radiation sensitivity.

   Evidence Co-IP, nuclear co-localization, siRNA knockdown with FANCI splice-variant analysis, cell cycle profiling, and clonogenic survival after ionizing radiation

   PMID:37168687

   Open questions at the time

   • No in vitro reconstitution of TXNL4B/PRP3 action on FANCI splicing
   • Direct catalytic or scaffolding role of TXNL4B not separated from PRP3 activity
   • Structural basis of TXNL4B–PRP3 interaction unknown

• How the homodimeric thioredoxin fold of TXNL4B is mechanistically deployed within the spliceosome, and whether it acts catalytically or as a scaffold, remains undefined.
• No co-complex structure with U5-102-kDa, PRP3, or other spliceosomal subunits
• No defined enzymatic activity for the thioredoxin fold
• Direct vs indirect contribution to DNA repair not resolved