Molecular basis of tail-anchored integral membrane protein recognition by the cochaperone Sgt2

Lin, Ku-Feng; Fry, Michelle Y.; Saladi, Shyam; Clemons, William M.

doi:10.1016/j.jbc.2021.100441

Cited by 16 publications

(26 citation statements)

References 91 publications

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“…Collectively, these datasets demonstrate that a fraction of the TMD is necessary and sufficient for correct localization. Interestingly, in the human dataset, some of the best performing metrics are limited to an 11‐residue window, concurring with reports that SGTA recognizes TMDs of at least 11 amino acids 12 …”

Section: Discussionsupporting

confidence: 84%

“…Furthermore, it was also reported that TMDs where the most hydrophobic residues cluster to one side of a helical wheel plot, 38 a 2D representation of an alpha‐helix, bind more efficiently to Sgt2 12 . We sought to examine if this clustering is a feature of ER TA proteins and absent in mitochondria TA proteins.…”

Section: Resultsmentioning

confidence: 98%

“…We wondered if TA protein classification could be improved by carefully assessing the hydrophobicity of the TMDs. Data showing that Sgt2 (a co‐chaperone in the GET pathway) binds a TMD of a minimal length of 11 residues suggests only a subset of each helix may be necessary to classify localization 12 . Indeed, the maximum hydrophobicity of segments, specified by the number residues selected, better classifies ER vs mitochondrial TA proteins across hydrophobicity scales (Figure 3A,B).…”

Section: Resultsmentioning

confidence: 99%

“…Applying the charge filter reveals that total hydrophobicity is as effective as hydrophobic face or segment metrics. Differences in the best performing hydrophobicity metrics between the yeast and human dataset could be explained by the observation that SGTA is more permissive to client binding than Sgt2 12 . Collectively, these datasets demonstrate that a fraction of the TMD is necessary and sufficient for correct localization.…”

Section: Discussionmentioning

confidence: 99%

“…Because of the position of their signals, TA proteins are translated by the ribosome and then post‐translationally targeted primarily to the endoplasmic reticulum (ER) or outer mitochondrial membrane. The TMD and C‐terminal residues following have been demonstrated to be necessary and sufficient for correct targeting in many experimental contexts 11,12 . Thus, it is suggested that the information recognized by TA protein targeting pathways is contained within the TMD and neighboring residues.…”

Section: Introductionmentioning

confidence: 99%

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Sequence‐based features that are determinant for tail‐anchored membrane protein sorting in eukaryotes

Fry

Saladi

Cunha³

et al. 2021

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The correct targeting and insertion of tail‐anchored (TA) integral membrane proteins is critical for cellular homeostasis. TA proteins are defined by a hydrophobic transmembrane domain (TMD) at their C‐terminus and are targeted to either the ER or mitochondria. Derived from experimental measurements of a few TA proteins, there has been little examination of the TMD features that determine localization. As a result, the localization of many TA proteins are misclassified by the simple heuristic of overall hydrophobicity. Because ER‐directed TMDs favor arrangement of hydrophobic residues to one side, we sought to explore the role of geometric hydrophobic properties. By curating TA proteins with experimentally determined localizations and assessing hypotheses for recognition, we bioinformatically and experimentally verify that a hydrophobic face is the most accurate singular metric for separating ER and mitochondria‐destined yeast TA proteins. A metric focusing on an 11 residue segment of the TMD performs well when classifying human TA proteins. The most inclusive predictor uses both hydrophobicity and C‐terminal charge in tandem. This work provides context for previous observations and opens the door for more detailed mechanistic experiments to determine the molecular factors driving this recognition.

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Section: Discussionsupporting

confidence: 84%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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