Abstract
Small glutamine-rich tetratricopeptide repeat-containing protein 2 (Sgt2) is a multi-module co-chaperone involved in several protein quality control pathways. The TPR domain of Sgt2 and several other proteins, including SGTA, Hop, and CHIP, is a highly conserved motif known to form transient complexes with molecular chaperones such as Hsp70 and Hsp90. In this work, we present the first high resolution crystal structures of Sgt2_TPR alone and in complex with a C-terminal peptide PTVEEVD from heat shock protein, Ssa1. Using nuclear magnetic resonance spectroscopy and isothermal titration calorimetry, we demonstrate that Sgt2_TPR interacts with peptides corresponding to the C-termini of Ssa1, Hsc82, and Ybr137wp with similar binding modes and affinities.
Highlights
Transient interactions between proteins confer functional versatility upon a range of cellular processes, including protein modification, transport, folding, and cell signaling pathways (Perkins et al, 2010)
The tetratricopeptide repeat (TPR) domain of Small glutamine-rich tetratricopeptide repeat-containing protein 2 (Sgt2) consists of three TPR repeats, comprising six almost identical α-helices and a C-terminal “capping” helix (α1 = A96-N115; α2 = Y118-V131; α3 = A136-L149; α4 = Y152-I165; α5 = F170-183Q; α6 = P186E200; α7 = E206-L225) connected by short loops and arranged in a antiparallel fold homologous to that of SGTA_TPR
In this study we provide high-resolution X-ray structures of the free Sgt2_TPR domain and its complex with the last seven amino acids of Ssa1 (Hsp70)
Summary
Transient interactions between proteins confer functional versatility upon a range of cellular processes, including protein modification, transport, folding, and cell signaling pathways (Perkins et al, 2010). TAs are a special case of membrane proteins with obscured targeting signals at the extreme C-terminus Their membrane delivery occurs post-translationally via the Guided Entry of Tail-anchored proteins pathway (GET; Schuldiner et al, 2008; Rabu et al, 2009; Borgese and Fasana, 2011; Hegde and Keenan, 2011). Sgt captures TA substrates after they are released from the ribosome and passes them on to the Get ATPase, the central targeting complex, in a process mediated by the Get4/Get heterodimeric scaffolding complex (Chartron et al, 2010; Wang et al, 2010; Simon et al, 2013; Mateja et al, 2015) This is followed by subsequent TA-protein release at the ER membrane, assisted by the Get1/Get heterodimeric membrane receptor complex (Wang et al, 2010; Mariappan et al, 2011; Vilardi et al, 2014).
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