International Journal of Molecular Sciences Review SRPassing Co-translational Targeting: The Role of the Signal Recognition Particle in Protein Targeting and mRNA Protection Morgana K. Kellogg, Sarah C. Miller, Elena B. Tikhonova and Andrey L. Karamyshev * Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; [email protected] (M.K.K.); [email protected] (S.C.M.); [email protected] (E.B.T.) * Correspondence: [email protected]; Tel.: +1-806-743-4102 Abstract: Signal recognition particle (SRP) is an RNA and protein complex that exists in all domains of life. It consists of one protein and one noncoding RNA in some bacteria. It is more complex in eukaryotes and consists of six proteins and one noncoding RNA in mammals. In the eukaryotic cyto- plasm, SRP co-translationally targets proteins to the endoplasmic reticulum and prevents misfolding and aggregation of the secretory proteins in the cytoplasm. It was demonstrated recently that SRP also possesses an earlier unknown function, the protection of mRNAs of secretory proteins from degradation. In this review, we analyze the progress in studies of SRPs from different organisms, SRP biogenesis, its structure, and function in protein targeting and mRNA protection. Keywords: ribosome; mRNA translation; signal recognition particle (SRP); protein targeting and transport; protein sorting; signal sequence; protein quality control; translational control Citation: Kellogg, M.K.; Miller, S.C.; Tikhonova, E.B.; Karamyshev, A.L. SRPassing Co-translational Targeting: 1. Introduction The Role of the Signal Recognition Cells have a very complex network of a number of cellular organelles surrounded Particle in Protein Targeting and by different membranes. To maintain their viability, cells constantly transport proteins mRNA Protection. Int. J. Mol. Sci. from the place of their synthesis to these organelles or outside of the cells. Cell proteomics 2021, 22, 6284. https://doi.org/ predicts that there are more than 109 proteins in a single human cell [1]. Therefore, directing 10.3390/ijms22126284 proteins to their correct destination is an important process for all cells. The correct identifi- cation and targeting of proteins are vital to ensure that the proteins are accurately folded, Academic Editor: Lasse Lindahl active, and delivered to the right place at the right time with the precise amount of protein needed. The cost of mistargeting, however, is large; many diseases are attributed to the Received: 30 April 2021 aberrant localization of proteins, which results in cytotoxic aggregation, degradation, loss Accepted: 5 June 2021 of expression, and misfolding of proteins. The cells have evolved several mechanisms and Published: 11 June 2021 many specific protein targeting signals to ensure fast, efficient, and accurate targeting of proteins to prevent these problems. In this review, we briefly discuss different protein tar- Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in geting signals and then focus on one of the major secretory pathways, the signal recognition published maps and institutional affil- particle (SRP) pathway, SRP biogenesis, SRP structure, and SRP cellular function. iations. 2. Protein Targeting Signals Proteins contain information about subcellular localization in the form of special sequences for their transport. Cells rely on the recognition of these specific signals (lo- calization sequences) embedded in the structure of polypeptide chains to sort proteins Copyright: © 2021 by the authors. to their appropriate cellular compartments. This recognition, targeting, and transport Licensee MDPI, Basel, Switzerland. This article is an open access article can occur during or after protein synthesis at the ribosome, and these pathways are distributed under the terms and referred to as co-translational and post-translational processes, respectively, shown in conditions of the Creative Commons Figure1A. Targeting to mitochondria, the nucleus, and peroxisomes occurs mostly post- Attribution (CC BY) license (https:// translationally, while protein targeting and importing into the endoplasmic reticulum creativecommons.org/licenses/by/ (ER) occurs co-translationally, directed by its cytosolic targeting factor, SRP, the signal 4.0/). recognition particle [2–7]. Int. J. Mol. Sci. 2021, 22, 6284. https://doi.org/10.3390/ijms22126284 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 22 Int. J. Mol. Sci. 2021, 22, 6284 while protein targeting and importing into the endoplasmic reticulum (ER) occurs co-transla-2 of 21 tionally, directed by its cytosolic targeting factor, SRP, the signal recognition particle [2–7]. FigureFigure 1. 1. CellularCellular organelles organelles and and protein protein target targetinging signals signals in inthe the mammalian mammalian cell. cell. (A) Protein (A) Protein tar- getingtargeting signals signals.. Within Within the cell, the cell,there there are many are many different different signals signals that direct that directproteins proteins for proper for proper local- ization.localization. Nuclear Nuclear (salmon (salmon circle) and circle) nucleolar and nucleolar (yellow (yellowcircle) signals circle) include signals the include NLS and the NES. NLS Sig- and nalsNES. to Signals the endoplasmic to the endoplasmic reticulum reticulum include the include signal the peptide signal and peptide KDEL, and which KDEL, prevents which secretion prevents fromsecretion the ER. from The the cytoplasmic ER. The cytoplasmic signals (light signals tan) (light are generally tan) are generally not well-defined not well-defined and include andinclude every- thingeverything that does that not does contain not contain a signal a signalpeptide. peptide. Peroxisome Peroxisome (purple (purple circle) circle)signals signals are PTS1 are and PTS1 PTS2. and The Golgi (magenta stacked ovals) signals include N-linked glycosylations, resident proteins are PTS2. The Golgi (magenta stacked ovals) signals include N-linked glycosylations, resident proteins retained via HEAT repeats, and errant proteins are recaptured with COPI and COPII vesicles. Tar- are retained via HEAT repeats, and errant proteins are recaptured with COPI and COPII vesicles. geting signals to the lysosome (gray circle) include phosphorylated mannose, or DXXLL or YXXφ. ' Post-translationalTargeting signals totargeting the lysosome to the (gray plasma circle) membrane include phosphorylated(black outline) uses mannose, the absence or DXXLL of mannose- or YXX . 6-p,Post-translational while co-translational targeting signals to the include plasma membranethe signal peptide. (black outline) Mitochondria uses the (blue) absence have of their mannose- own mitochondrial6-p, while co-translational targeting signal signals peptide. include Extracellu the signallar matrix-bound peptide. Mitochondria proteins (white (blue) background) have their own are targetedmitochondrial using a targeting signal peptide. signal peptide. All co-translation Extracellularal mechanisms matrix-bound of targeting proteins (white are designated background) by two are starstargeted flanking using the a signal signal peptide. (e.g., *signal All co-translational peptide*). (B) Diagram mechanisms of a ofprotein targeting with are a signal designated sequence by two. A signalstars flanking sequence the features signal a (e.g., positi *signalve N-region peptide*). (yellow), (B) Diagram a hydrophobic of a protein (H) middle with a signalregion sequence. (blue), a C- A regionsignal sequence(green), and features a region a positive that will N-region become (yellow),the mature a hydrophobic protein once (H)signal middle peptidase region (cleavage (blue), a site demarcated by black triangles) cleaves off the signal sequence (red). C-region (green), and a region that will become the mature protein once signal peptidase (cleavage site demarcated by black triangles) cleaves off the signal sequence (red). Post-translational targeting includes signals to the peroxisome, nuclear entrance and exit signals,Post-translational Golgi membrane targeting localization, includes signalssignals toto thethe peroxisome,lysosome, and nuclear mitochondrial entrance andsig- nalexit peptides. signals, Golgi Many membrane post-translational localization, targetin signalsg features to the lysosome, have been and characterized. mitochondrial Peroxi- signal somespeptides. have Many two signals: post-translational peroxisome targeting targeting features signal have1 (PTS1) been and characterized. 2 (PTS2). The Peroxisomes most com- monhave PTS1 two signals:signal is peroxisome a serine-lysine-leucine targeting signal at the 1 carboxy-end (PTS1) and 2 [8] (PTS2). and is The recognized most common by the PTS1 signal is a serine-lysine-leucine at the carboxy-end [8] and is recognized by the recep- tor encoded by PEX5 on the peroxisomal membrane [9]. PTS2 uses the PEX5L and PEX7 receptors in mammals for transport into the peroxisome [10]. Nuclear targeting signals Int. J. Mol. Sci. 2021, 22, 6284 3 of 21 have both entry and exit codes: a nuclear localization signal (NLS) to target the nucleus and a nuclear exit signal (NES) to leave. Nuclear localization signals have a general consensus sequence featuring positively charged amino acids with linker regions in between, called a bipartite signal [11]. Importins, either by themselves or with cofactors, recognize NLSs to permit proteins to enter the nucleus. Nuclear exit signals consist of four