Being phosphopeptide-binding hubs, 14-3-3 proteins coordinate multiple cellular processes in eukaryotes, including the regulation of apoptosis, cell cycle, ion channels trafficking, transcription, signal transduction, and hormone biosynthesis. Forming constitutive α-helical dimers, 14-3-3 proteins predominantly recognize specifically phosphorylated Ser/Thr sites within their partners; this generally stabilizes phosphotarget conformation and affects its activity, intracellular distribution, dephosphorylation, degradation and interactions with other proteins. Not surprisingly, 14-3-3 complexes are involved in the development of a range of diseases and are considered promising drug targets. The wide interactome of 14-3-3 proteins encompasses hundreds of different phosphoproteins, for many of which the interaction is well-documented in vitro and in vivo but lack the structural data that would help better understand underlying regulatory mechanisms and develop new drugs. Despite obtaining structural information on 14-3-3 complexes is still lagging behind the research of 14-3-3 interactions on a proteome-wide scale, recent works provided some advances, including methodological improvements and accumulation of new interesting structural data, that are discussed in this review. 

Recent advances in structural studies of 14-3-3 protein complexes.

The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as 'undruggable' targets and the design of PPIs stabilizers remains a significant challenge. The application of fragment-based methods for the identification of drug leads and to evaluate the 'tractability' of the desired protein target has seen a remarkable development in recent years. In this study, we explore the molecular characteristics of the 14-3-3/Amot-p130 PPI and the conceptual possibility of targeting this interface using X-ray crystallography fragment-based screening. We report the first structural elucidation of the 14-3-3 binding motif of Amot-p130 and the characterization of the binding mode and affinities involved. We made use of fragments to probe the 'ligandability' of the 14-3-3/Amot-p130 composite binding pocket. Here we disclose initial hits with promising stabilizing activity and an early-stage selectivity toward the Amot-p130 motifs over other representatives 14-3-3 partners. Our findings highlight the potential of using fragments to characterize and explore proteins' surfaces and might provide a starting point toward the development of small molecules capable of acting as molecular glues. 

Fragment-based exploration of the 14-3-3/Amot-p130 interface

http://www.cell.com/article/S2211124722005174/pdf

Clearance of an amyloid-like translational repressor is governed by 14–3–3 proteins

Cancer cells prefer glycolysis to support their proliferation. Our previous studies have shown that the long palate, lung, and nasal epithelial cell clone 1 (LPLUNC1) can upregulate prohibitin 1 (PHB1) expression to inhibit the proliferation of nasopharyngeal carcinoma (NPC) cells. Given that PHB1 is an important regulator of cell energy metabolism, we explored whether and how LPLUNC1 regulated glucose glycolysis in NPC cells. LPLUNC1 or PHB1 overexpression decreased glycolysis and increased oxidative phosphorylation (OXPHOS)‐related protein expression in NPC cells, promoting phosphorylated PHB1 nuclear translocation through 14‐3‐3σ. LPLUNC1 overexpression also increased p53 but decreased c‐Myc expression in NPC cells, which were crucial for the decrease in glycolysis and increase in OXPHOS‐related protein expression induced by LPLUNC1 overexpression. Finally, we found that treatment with all‐trans retinoic acid (ATRA) reduced the viability and clonogenicity of NPC cells, decreased glycolysis, and increased OXPHOS‐related protein expression by enhancing LPLUNC1 expression in NPC cells. Therefore, the LPLUNC1‐PHB1‐p53/c‐Myc axis decreased glycolysis in NPC cells, and ATRA upregulated LPLUNC1 expression, ATRA maybe a promising drug for the treatment of NPC.

/pdf/lplunc1-reduces-glycolysis-in-nasopharyngeal-carcinoma-cells-3azm341x.pdf

LPLUNC1 reduces glycolysis in nasopharyngeal carcinoma cells through the PHB1‐p53/c‐Myc axis

http://www.jbc.org/article/S0021925823018835/pdf

Rachel Davis

Papers

A Structural Study of the Cytoplasmic Chaperone Effect of 14-3-3 Proteins on Ataxin-1