bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2022‒12‒18
two papers selected by
Thomas Farid Martínez
University of California, Irvine

  1. RNA. 2022 Dec 14. pii: rna.079462.122. [Epub ahead of print]
      The eukaryotic initiation factor 4G2 (eIF4G2, DAP5, Nat1, p97) was discovered in 1997. Over the past two decades, dozens of papers have presented contradictory data on eIF4G2 function. Since its identification, eIF4G2 has been assumed to participate in noncanonical translation initiation mechanisms, but recent results indicate that it can be involved in scanning as well. In particular, eIF4G2 provides leaky scanning through some upstream open reading frames (uORFs), which are typical for long 5' UTRs of mRNAs from higher eukaryotes. It is likely the protein can also help the ribosome overcome other impediments during scanning of the 5' UTRs of animal mRNAs. This may explain the need for eIF4G2 in higher eukaryotes, as many mRNAs that encode regulatory proteins have rather long and highly structured 5' UTRs. Additionally, they often bind to various proteins, which also hamper the movement of scanning ribosomes. This review discusses the suggested mechanisms of eIF4G2 action, denotes obscure or inconsistent results, and proposes ways to uncover other fundamental mechanisms in which this important protein factor may be involved in higher eukaryotes.
    Keywords:  cap-dependent translation; cap-independent translation; cellular IRES; eIF4F; ribosome collision
  2. Biophys J. 2022 Dec 14. pii: S0006-3495(22)03924-8. [Epub ahead of print]
      The sarco(endo)plasmic reticulum calcium ATPase (SERCA) is an ion transporter that creates and maintains intracellular calcium stores. SERCA is inhibited or stimulated by several membrane micropeptides including another-regulin (ALN), dwarf open reading frame (DWORF), endoregulin (ELN), phospholamban (PLB), and sarcolipin (SLN). We previously showed these micropeptides assemble into homo-oligomeric complexes with varying affinity. Here we tested whether different micropeptides can interact with each other, hypothesizing that co-assembly into hetero-oligomers may affect micropeptide bioavailability to regulate SERCA. We quantified the relative binding affinity of each combination of candidates using automated fluorescence resonance energy transfer (FRET) microscopy. All pairs were capable of interacting with good affinity, similar to that of to self-binding (homo-oligomerization). Testing each pair at a 1:5 ratio and a reciprocal 5:1 ratio, we noted that the affinity of hetero-oligomerization of some micropeptides depended on whether they were the minority or majority species. In particular, SLN was able to join oligomers when it was the minority species, but did not readily accommodate other micropeptides in the reciprocal experiment when it was expressed in 5-fold excess. The opposite was observed for ELN. PLB was a universal partner for all other micropeptides tested, forming avid hetero-oligomers whether it was the minority or majority species. Increasing expression of SERCA decreased PLB-DWORF hetero-oligomerization, suggesting that SERCA-micropeptide interactions compete with micropeptide-micropeptide interactions. Thus, micropeptides populate a regulatory network of diverse protein assemblies. The data suggest that the complexity of this interactome increases exponentially with the number of micropeptides that are coexpressed in a particular tissue.