Hide and run. Arginine-based endoplasmic-reticulum-sorting motifs in the assembly of heteromultimeric membrane proteins - PubMed (original) (raw)

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Hide and run. Arginine-based endoplasmic-reticulum-sorting motifs in the assembly of heteromultimeric membrane proteins

Kai Michelsen et al. EMBO Rep. 2005 Aug.

Abstract

Arginine-based endoplasmic reticulum (ER)-localization signals are sorting motifs that are involved in the biosynthetic transport of multimeric membrane proteins. After their discovery in the invariant chain of the major histocompatibility complex class II, several hallmarks of these signals have emerged. They occur in polytopic membrane proteins that are subunits of membrane protein complexes; the presence of the signal maintains improperly assembled subunits in the ER by retention or retrieval until it is masked as a result of heteromultimeric assembly. A distinct consensus sequence and their position independence with respect to the distal termini of the protein distinguish them from other ER-sorting motifs. Recognition by the coatomer (COPI) vesicle coat explains ER retrieval. Often, di-leucine endocytic signals occur close to arginine-based signals. Recruitment of 14-3-3 family or PDZ-domain proteins can counteract ER-localization activity, as can phosphorylation. This, and the occurrence of arginine-based signals in alternatively spliced regions, implicates them in the regulated surface expression of multimeric membrane proteins in addition to their function in quality control.

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Figures

Figure 1

Figure 1

Arginine-based signals in proteins of different topology. Numbers indicate the size of cytosolic domains and the first Arg residue of the Arg-based signal. Arg-based signals are indicated in red. (A) Invariant chain Ii p35 of major histocompatibility complex (MHC) class II (p35 is one of two variants owing to the use of alternative initiator methionines). (B) γ-aminobutyric acid (GABAB) receptor subunit 1. The zigzag line indicates a coiled-coil forming domain. (C) Kir6.2 is the pore-forming subunit of the KATP channel. (D) SUR1 is the regulatory subunit of the KATP channel. (E) Glycoprotein B from human cytomegalovirus (HCMV). (F) N-methyl

D

-aspartate (NMDA) receptor subunit NR1-1.

Figure 2

Figure 2

Model of KATP channel transport. Larger and smaller rectangular shapes represent the SUR1 and Kir6.2 subunits, respectively. Arginine (Arg)-based signals are shown as red dots. 14-3-3 proteins are depicted as joined brackets. These proteins have been implicated in the forward transport of KATP channels (Yuan et al, 2003), but their exact role is unclear (Nufer & Hauri, 2003). A di-leucine endocytosis signal in the vicinity of the Arg-based signal has been shown to mediate dynamin-dependent endocytosis (Hu et al, 2003). COPI, coat protein complex I; ER, endoplasmic reticulum.

Figure 3

Figure 3

Mechanisms for the masking of arginine-based signals. Red dots symbolize the Arg-based signals. (A) Steric masking: coiled-coil forming domains in the two γ-aminobutyric acid (GABAB) receptor subunits hide the signal present in GABAB R1-subunit (Margeta-Mitrovic et al, 2000). (B) Phosphorylation of a residue in the vicinity of the Arg-based signal in the major histocompatibility complex (MHC) invariant chain recruits 14-3-3 proteins (joined brackets), which leads to signal shielding (Kuwana et al, 1998). Heteromultimeric assembly with MHC class II βsubunit also leads to steric masking (Khalil et al, 2003). How the two mechanisms relate to each other is unclear. (C) Masking by a PDZ-domain protein (large bracket) binding to the distal C-terminus of N-methyl

D

-aspartate receptor subunit NR1-3 (Standley et al, 2000).

None

Kai Michelsen, Blanche Schwappach and Hebao Yuan. B.S. is the recipient of an EMBO Young Investigator award.

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