Structural basis of signal-sequence recognition by the signal recognition particle

Hainzl, Tobias; Huang, Sijia; Meriläinen, Gitte; Brännström, Kristoffer; Sauer‐Eriksson, A. Elisabeth

doi:10.1038/nsmb.1994

Cited by 71 publications

(105 citation statements)

References 18 publications

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“…FtsY and Ffh interact via their homologous NG domains and form a composite GTPase active site (10, 11). Crystal structures of the M domain reveal a hydrophobic groove used to capture signal sequences (4,5,12).Protein targeting is driven by highly regulated conformational rearrangements of SRP and FtsY as well as GTP hydrolysis. SRP recognizes and tightly binds to RNCs displaying a signal sequence (cargo).…”

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confidence: 99%

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“…Ffh is composed of the N-terminal domain, the G domain that harbors GTPase activity, and the C-terminal methionine-rich M domain that interacts with 4.5S RNA (2,3) and with the signal sequence (4,5). The N and G domains form a compact structural and functional unit termed "the NG domain."…”

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confidence: 99%

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Ribosome–SRP–FtsY cotranslational targeting complex in the closed state

Loeffelholz

Jiang

Ariosa

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The signal recognition particle (SRP)-dependent pathway is essential for correct targeting of proteins to the membrane and subsequent insertion in the membrane or secretion. In Escherichia coli, the SRP and its receptor FtsY bind to ribosome-nascent chain complexes with signal sequences and undergo a series of distinct conformational changes, which ensures accurate timing and fidelity of protein targeting. Initial recruitment of the SRP receptor FtsY to the SRP-RNC complex results in GTP-independent binding of the SRP-FtsY GTPases at the SRP RNA tetraloop. In the presence of GTP, a closed state is adopted by the SRP-FtsY complex. The cryo-EM structure of the closed state reveals an ordered SRP RNA and SRP M domain with a signal sequence-bound. Van der Waals interactions between the finger loop and ribosomal protein L24 lead to a constricted signal sequence-binding pocket possibly preventing premature release of the signal sequence. Conserved M-domain residues contact ribosomal RNA helices 24 and 59. The SRP-FtsY GTPases are detached from the RNA tetraloop and flexible, thus liberating the ribosomal exit site for binding of the translocation machinery.protein targeting | signal recognition particle | signal sequence | ribosome | single-particle electron cryomicroscopy T he Escherichia coli signal recognition particle (SRP) is a complex consisting of the universally conserved protein Ffh and 4.5S RNA, which adopts a hairpin structure (1). Ffh is composed of the N-terminal domain, the G domain that harbors GTPase activity, and the C-terminal methionine-rich M domain that interacts with 4.5S RNA (2, 3) and with the signal sequence (4, 5). The N and G domains form a compact structural and functional unit termed "the NG domain." Targeting of ribosome-nascent chain complexes (RNC) containing a signal sequence depends on the interaction of the RNC-SRP complex with the SRP receptor FtsY, which is membrane associated (6-9). FtsY and Ffh interact via their homologous NG domains and form a composite GTPase active site (10, 11). Crystal structures of the M domain reveal a hydrophobic groove used to capture signal sequences (4,5,12).Protein targeting is driven by highly regulated conformational rearrangements of SRP and FtsY as well as GTP hydrolysis. SRP recognizes and tightly binds to RNCs displaying a signal sequence (cargo). Next, RNC-bound SRP efficiently recruits FtsY to form a nucleotide-independent, transient early state that rearranges to a GTP-stabilized closed state (13). Ultimately, in the activated state, handover of the RNC to the Sec translocon takes place, followed by GTP hydrolysis and disassembly of the SRP-FtsY complex (14-16). These distinct conformational transitions are regulated by the ribosome and translocon in the membrane, leading to a switch from cargo recognition by SRP to cargo release (17, 18).Cryo-EM structures of bacterial SRP-bound RNCs revealed a tight cargo-recognition complex (19,20). In the SRP-FtsY early complex an overall detachment of SRP from the ribosome was observed (21). In this sta...

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Ribosome–SRP–FtsY cotranslational targeting complex in the closed state

Loeffelholz

Jiang

Ariosa

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…By studying crystal structures of the SRP RNA in complex with its different protein partners, many of the structural states of the SRP have been revealed. The structures of the Methanococcus jannaschii SRP54-SRP19-S domain RNA complex in its free form [1] and in complex with an hydrophobic idealized signal peptide comprising 14 leucine and alanine residues [2] provide an explanation for how signal peptide binding at the M domain triggers a reorientation of the GTPase domain by local structuring and a-helix formation of the GM linker. …”

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“…In Dsr-II, the thioether bond is broken, and the Cysg104 side chain moves closer to the bound sulfite at the siroheme pocket. These different forms of Dsr offer structural insights into a mechanism of sulfite reduction that can lead to S 3 O 6 2-, S 2 O 3 2-and S 2- [2]. The signal recognition particle (SRP) recognizes and binds to the signal peptide of nascent proteins as they emerge from the ribosome.…”

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Structural basis of signal peptide recognition by the signal recognition particle

Sauer-Eriksson¹,

Huang²,

Meriläinen³

et al. 2012

Acta Cryst Sect A

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Sulfate-reducing bacteria (SRB), the strict anaerobes, constitute a particular group of prokaryotes that can metabolize sulfate. In dissimilatory sulfate reduction, the activation of sulfate is first catalyzed by ATP sulphurylase to produce adenosine 5'-phosphosulfate (APS), which is then reduced by adenylylsulfate reductase (adenosine 5'-phosphosulfate reductase, APS reductase or APSR) to sulfite. Sulfite is subsequently reduced by dissimilatory sulfite reductase (Dsr) to three products: trithionate (S 3 O 6 2-), thiosulfate (S 2 O 3 2-) or sulfide (S 2-). We have determined crystal structures of APSR and Dsr from Desulfovibrio gigas, a much studied representatives of SRB. APSR comprises six ab-heterodimers that form a hexameric structure. The flavin adenine dinucleotide (FAD) is non-covalently attached to the a-subunit, and two [4Fe-4S] clusters are enveloped by cluster-binding motifs. The C-terminal segment of the b-subunit wraps around the á-subunit to form a functional unit, with the C-terminal loop inserted into the active-site channel of the á-subunit from another ab-heterodimer. The structure of APSR, together with its oligomerization properties, suggests that APSR might self-regulate its activity through the C-terminus of the b-subunit [1, 3]. The structures of two active forms of Dsr, Dsr-I and Dsr-II, are also determined and compared. The dimeric a 2 b 2 g 2 structure of Dsr-I contains eight [4Fe-4S] clusters, two saddle-shaped sirohemes and two flat sirohydrochlorins. In Dsr-II, the [4Fe-4S] cluster associated with the siroheme in Dsr-I is replaced by a [3Fe-4S] cluster. The g-subunit C-terminus is inserted into a positively charged channel formed between the a-and b-subunits, with its conserved terminal Cysg104 side chain covalently linked to the CHA atom of the siroheme in Dsr-I. In Dsr-II, the thioether bond is broken, and the Cysg104 side chain moves closer to the bound sulfite at the siroheme pocket. These different forms of Dsr offer structural insights into a mechanism of sulfite reduction that can lead to S 3 O 6 2-, S 2 O 3 2-and S 2-[2]. The signal recognition particle (SRP) recognizes and binds to the signal peptide of nascent proteins as they emerge from the ribosome. The conserved core of SRP consists of SRP RNA and the SRP54 protein, and plays the key role in signal-peptide recognition and binding to the SRP receptor. Proper communication between the two SRP54 domains, the GTPase-and the M-domain, is vital for the function of the particle so that signal-peptide binding at the M domain directs receptor binding at the GTPase domain. By studying crystal structures of the SRP RNA in complex with its different protein partners, many of the structural states of the SRP have been revealed. The structures of the Methanococcus jannaschii SRP54-SRP19-S domain RNA complex in its free form [1] and in complex with an hydrophobic idealized signal peptide comprising 14 leucine and alanine residues [2] provide an explanation for how signal peptide binding at the M domain triggers a reorientation of th...

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hSnd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells

et al. 2017

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Recently, understanding of protein targeting to the endoplasmic reticulum (ER) was expanded by the discovery of multiple pathways that function in parallel to the signal recognition particle (SRP). Guided entry of tail-anchored proteins and SRP independent (SND) are two such targeting pathways described in yeast. So far, no human SND component is functionally characterized. Here, we report hSnd2 as the first constituent of the human SND pathway able to support substrate-specific protein targeting to the ER. Similar to its yeast counterpart, hSnd2 is assumed to function as a membrane-bound receptor preferentially targeting precursors carrying C-terminal transmembrane domains. Our genetic and physical interaction studies show that hSnd2 is part of a complex network of targeting and translocation that is dynamically regulated.

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Structural basis of signal-sequence recognition by the signal recognition particle

Cited by 71 publications

References 18 publications

Ribosome–SRP–FtsY cotranslational targeting complex in the closed state

Ribosome–SRP–FtsY cotranslational targeting complex in the closed state

Structural basis of signal peptide recognition by the signal recognition particle

hSnd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells

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