Fidelity of Cotranslational Protein Targeting by the Signal Recognition Particle

Abstract

Accurate folding, assembly, localization and maturation of newly synthesized proteins are essential to all cells and requires a high fidelity in the protein biogenesis machineries that mediate these processes. Here, we review our current understanding on how high fidelity is achieved in one of these processes, the co-translational targeting of nascent membrane and secretory proteins by the signal recognition particle (SRP). Recent biochemical, biophysical, and structural studies have elucidated how the correct substrates drive a series of elaborate conformational rearrangements in the SRP and SRP receptor GTPases, which provide effective fidelity checkpoints to reject incorrect substrates and enhance the fidelity of this essential cellular pathway. The mechanisms used by the SRP to ensure fidelity share important conceptual analogies with those used by cellular machineries involved in DNA replication, transcription and translation, and likely represent general principles for other complex cellular pathways.

Defining the physiological role of SRP in protein-targeting efficiency and specificity

“…The role of the signal recognition particle (SRP) in mediating cotranslational ER targeting is well established. SRP recognizes N-terminal hydrophobic signals of nascent polypeptide chains and, through interaction with the ER-localized SRP receptor, directs them to the translocon (1). …”

Multiple selection filters ensure accurate tail-anchored membrane protein targeting

“…First, topogenic signals that define a protein’s final destination tend to be degenerate and lack consensus motifs (von Heijne, 1985; Zheng and Gierasch, 1996), which demands targeting machineries to be adaptable and able to recognize a diverse set of signals. Second, minor differences in targeting signals distinguish proteins that belong to alternative pathways or organelles (Emanuelsson and von Heijne, 2001; von Heijne, 1985; Zhang and Shan, 2014; Zheng and Gierasch, 1996). Thus, protein-targeting pathways must also evolve robust selection mechanisms that can detect these minor differences.…”

“…Furthermore, hydrophobic transmembrane domains (TMDs) on membrane protein substrates are prone to irreversible aggregation that can lead to mislocalization and proteostatic stress, requiring targeting machineries to also effectively shield the TMDs during targeting (Shao and Hegde, 2011). Except for a few systems (see [Randall and Hardy, 1995; Zhang and Shan, 2014]), the molecular mechanisms by which protein targeting machineries overcome these challenges are not well understood for most pathways.…”

Cotranslational signal-independent SRP preloading during membrane targeting

“…It is unclear how the low complexity information exposed by the nascent chain suffices for accurate recognition by the many factors competing for the limited surface near the ribosomal exit site 2,3 . Questions remain even for the well-studied cotranslational targeting cycle to the endoplasmic reticulum (ER), involving recognition of linear hydrophobic Signal Sequences (SS) or Transmembrane Domains (TMD) by the Signal Recognition Particle (SRP) 4,5 . Intriguingly, SRP is in low abundance relative to the large number of ribosome nascent chain complexes (RNCs), yet it accurately selects those destined to the ER 6 .…”