Fig. 6: Model for eEF1A biogenesis.
From: Chp1 is a dedicated chaperone at the ribosome that safeguards eEF1A biogenesis
(1) Chp1 scans ribosome-nascent chain complexes. (2) Upon emergence of the first N-terminal 70 amino acids of nascent eEF1A (β1-α1-α2-α3) outside the ribosomal tunnel, Chp1 engages the nascent polypeptide by direct binding. (3) Chp1 remains bound to nascent eEF1A during the synthesis of the GTPase domain (domain I) and stabilizes it. Direct binding between Chp1 and the α-subunit of NAC through its UBA domain helps to stabilize Chp1 interaction with the ribosome- eEF1A domain I nascent chain complex. (4) Chp1 releases eEF1A nascent chain once the GTPase domain is completely translated, exposed out of the ribosomal tunnel and folded into its native stable conformation. (5) Following the expression of domains II and III, the Zpr1 chaperone and its cochaperone Aim29 mediate the downstream folding of the newly synthesized eEF1A into its final native conformation17,18. (Low-left inset:) Failure to recruit Chp1 (chp1Δ) during eEF1A biosynthesis impedes the folding of the GTPase domain and eEF1A is targeted to proteolysis by the 26S proteasome via polyubiquitylation. The high rates of aberrant eEF1A translation results in a heavy load on the proteostasis system; cells accumulate protein aggregates and activate Hsf1-mediated transcription that is responsive to the accumulation of misfolded proteins. (Low-right inset:) Chp1 binds fully synthesized eEF1A F98C which is an unstable variant of eEF1A associated to epileptic-dyskinetic encephalopathy in humans. Interaction of Chp1 with fully synthesized eEF1A F98C increases the stability of the mutant variant and protects it from proteosomal degradation.
