7Q16

Human 14-3-3 zeta fused to the BAD peptide including phosphoserine-74

Summary for 7Q16

• Entry DOI: 10.2210/pdb7q16/pdb
• Descriptor: 14-3-3 protein zeta/delta,Bcl2-associated agonist of cell death (2 entities in total)
• Functional Keywords: signaling protein, apoptotic regulation, phosphorylation, phosphopeptide binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 27552.87

Authors

Sluchanko, N.N.,Tugaeva, K.V.,Gushchin, I.,Remeeva, A.,Kovalev, K.,Cooley, R.B. (deposition date: 2021-10-18, release date: 2021-11-17, Last modification date: 2024-11-20)

Primary citation

Sluchanko, N.N.,Tugaeva, K.V.,Gushchin, I.,Remeeva, A.,Kovalev, K.,Cooley, R.B.
Crystal structure of human 14-3-3 zeta complexed with the noncanonical phosphopeptide from proapoptotic BAD.
Biochem.Biophys.Res.Commun., 583:100-105, 2021

PubMed Abstract: Several signaling pathways control phosphorylation of the proapoptotic protein BAD and its phosphorylation-dependent association with 14-3-3 proteins in the cytoplasm. The stability of the 14-3-3/BAD complex determines the cell fate: unphosphorylated BAD escapes from 14-3-3, migrates to the mitochondria and initiates apoptosis. While the 14-3-3/BAD interaction represents a promising drug target, it lacks structural characterization. Among several phosphosites identified in vivo, Ser75 and Ser99 of human BAD match the consensus sequence RXXpSXP recognized by 14-3-3 and, therefore, represent canonical 14-3-3-binding sites. Yet, BAD contains other serines phosphorylatable in vivo, whose role is less understood. Here, we report a 2.36 Å crystal structure of 14-3-3ζ complexed with a BAD fragment which includes residues Ser74 and Ser75, both being substrates for protein kinases. While the BAD peptide is anchored to 14-3-3 by phosphoserine as expected, the BAD peptide was unexpectedly phosphorylated at Ser74 instead of Ser75, revealing noncanonical binding within the amphipathic groove and leading to a one-step positional shift and reorganization of the interface. This observation exemplifies plasticity of the amphipathic 14-3-3 groove in accommodating various peptides and suggests the redundancy of Ser74 and Ser75 phosphosites with respect to binding of BAD to 14-3-3.

PubMed: 34735870
DOI: 10.1016/j.bbrc.2021.10.053

Experimental method

X-RAY DIFFRACTION (2.356 Å)