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The concept of translocational regulation.

Hegde RS, Kang SW - J. Cell Biol. (2008)

Bottom Line: Biological processes are regulated to provide cells with exquisite adaptability to changing environmental conditions and cellular demands.The mechanisms regulating secretory and membrane protein translocation into the endoplasmic reticulum (ER) are unknown.A conceptual framework for translocational regulation is proposed based on our current mechanistic understanding of ER protein translocation and general principles of regulatory control.

View Article: PubMed Central - PubMed

Affiliation: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. hegder@mail.nih.gov

ABSTRACT
Biological processes are regulated to provide cells with exquisite adaptability to changing environmental conditions and cellular demands. The mechanisms regulating secretory and membrane protein translocation into the endoplasmic reticulum (ER) are unknown. A conceptual framework for translocational regulation is proposed based on our current mechanistic understanding of ER protein translocation and general principles of regulatory control.

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Related in: MedlinePlus

A dynamic signal–Sec61 interaction. After targeting to the Sec61 complex (top), the signal sequence is proposed to interact weakly and dynamically with the putative signal binding site on Sec61. The looped (right) and nonlooped (left) configurations are more interconvertible at shorter nascent chain lengths than at longer lengths.
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fig2: A dynamic signal–Sec61 interaction. After targeting to the Sec61 complex (top), the signal sequence is proposed to interact weakly and dynamically with the putative signal binding site on Sec61. The looped (right) and nonlooped (left) configurations are more interconvertible at shorter nascent chain lengths than at longer lengths.

Mentions: Assuming that signals interact with Sec61 analogously to TMDs, variability in translocation efficiencies among signals could be due in part to the efficiency with which different signals adopt the correct looped orientation in the channel (Fig. 2). In the same way that TMD orientation is influenced by its length, hydrophobic domain, and flanking regions (Higy et al., 2004), analogous differences among signals may affect their affinity, stability, and mode of interaction with Sec61. When positioned in the looped orientation, elongation of the nascent chain results in its entry into the ER lumen. Interaction in a nonlooped orientation forces the mature domain of a nascent chain to be extruded into the cytosol. Presumably, these configurations are dynamic, and the nascent chain not only samples both orientations but can switch between them at early stages of translocation (as suggested for TMDs by Goder et al. [1999]). However, increasing nascent chain length upon continued translation would decrease the capacity to change orientations, eventually resulting in “commitment” to either forward or failed translocation. The decisive point (i.e., nascent chain length) at which commitment occurs would depend on properties of both the signal sequence (its affinity for and stability within the translocon) and mature domain (its capacity to remain sufficiently unfolded to pass through the translocon). This commitment point would therefore vary from substrate to substrate, giving each a somewhat different period of time to be biased in one direction or another (as elaborated in the subsequent section).


The concept of translocational regulation.

Hegde RS, Kang SW - J. Cell Biol. (2008)

A dynamic signal–Sec61 interaction. After targeting to the Sec61 complex (top), the signal sequence is proposed to interact weakly and dynamically with the putative signal binding site on Sec61. The looped (right) and nonlooped (left) configurations are more interconvertible at shorter nascent chain lengths than at longer lengths.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2483521&req=5

fig2: A dynamic signal–Sec61 interaction. After targeting to the Sec61 complex (top), the signal sequence is proposed to interact weakly and dynamically with the putative signal binding site on Sec61. The looped (right) and nonlooped (left) configurations are more interconvertible at shorter nascent chain lengths than at longer lengths.
Mentions: Assuming that signals interact with Sec61 analogously to TMDs, variability in translocation efficiencies among signals could be due in part to the efficiency with which different signals adopt the correct looped orientation in the channel (Fig. 2). In the same way that TMD orientation is influenced by its length, hydrophobic domain, and flanking regions (Higy et al., 2004), analogous differences among signals may affect their affinity, stability, and mode of interaction with Sec61. When positioned in the looped orientation, elongation of the nascent chain results in its entry into the ER lumen. Interaction in a nonlooped orientation forces the mature domain of a nascent chain to be extruded into the cytosol. Presumably, these configurations are dynamic, and the nascent chain not only samples both orientations but can switch between them at early stages of translocation (as suggested for TMDs by Goder et al. [1999]). However, increasing nascent chain length upon continued translation would decrease the capacity to change orientations, eventually resulting in “commitment” to either forward or failed translocation. The decisive point (i.e., nascent chain length) at which commitment occurs would depend on properties of both the signal sequence (its affinity for and stability within the translocon) and mature domain (its capacity to remain sufficiently unfolded to pass through the translocon). This commitment point would therefore vary from substrate to substrate, giving each a somewhat different period of time to be biased in one direction or another (as elaborated in the subsequent section).

Bottom Line: Biological processes are regulated to provide cells with exquisite adaptability to changing environmental conditions and cellular demands.The mechanisms regulating secretory and membrane protein translocation into the endoplasmic reticulum (ER) are unknown.A conceptual framework for translocational regulation is proposed based on our current mechanistic understanding of ER protein translocation and general principles of regulatory control.

View Article: PubMed Central - PubMed

Affiliation: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. hegder@mail.nih.gov

ABSTRACT
Biological processes are regulated to provide cells with exquisite adaptability to changing environmental conditions and cellular demands. The mechanisms regulating secretory and membrane protein translocation into the endoplasmic reticulum (ER) are unknown. A conceptual framework for translocational regulation is proposed based on our current mechanistic understanding of ER protein translocation and general principles of regulatory control.

Show MeSH
Related in: MedlinePlus