Biol. Chem. 2014; 395(12): 1365–1377
Review Grant Kemp and Florian Cymer*
Small membrane proteins – elucidating the function of the needle in the haystack Abstract: Membrane proteins are important mediators between the cell and its environment or between different compartments within a cell. However, much less is known about the structure and function of membrane proteins compared to water-soluble proteins. Moreover, until recently a subset of membrane proteins, those shorter than 100 amino acids, have almost completely evaded detection as a result of technical difficulties. These small membrane proteins (SMPs) have been underrepresented in most genomic and proteomic screens of both pro- and eukaryotic cells and, hence, we know much less about their functions in both. Currently, through a combination of bioinformatics, ribosome profiling, and more sensitive proteomics, large numbers of SMPs are being identified and characterized. Herein we describe recent advances in identifying SMPs from genomic and proteomic datasets and describe examples where SMPs have been successfully characterized biochemically. Finally we give an overview of identified functions of SMPs and speculate on the possible roles SMPs play in the cell. Keywords: AcrZ; transmembrane.
KdpF;
phospholamban;
sORF;
DOI 10.1515/hsz-2014-0213 Received June 16, 2014; accepted August 6, 2014; previously published online August 12, 2014
Introduction Cellular membranes define the borders of cells. They allow the ordered intracellular space to exist next to the relatively disordered extracellular environment and separate *Corresponding author: Florian Cymer, Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden, e-mail: [email protected] Grant Kemp: Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden
the distinct microenvironments of intracellular organelles within a cell. Cellular membranes are composed of a defined lipid bilayer embedded with membrane proteins that allow the selective exchange of signals or substances between cellular compartments or the extracellular space. Indeed, the importance of membrane proteins is highlighted by the fact that nearly half of current therapeutic targets are membrane proteins (Hopkins and Groom, 2002). However, the difficulty of working with these proteins has resulted in our understanding of soluble proteins far exceeding that of membrane proteins. It is still not completely clear how membrane proteins are synthesized in a cell, how they are inserted into a membrane, how they fold and how they are eventually removed from a membrane and degraded (Brodsky, 2012; Apaja and Lukacs, 2014; Lee and Kim, 2014; Popot, 2014). Genomic screens indicate that about a quarter of all proteins in a cell are membrane proteins (Babcock and Li, 2014). While significant effort is being applied to increase our understanding of membrane protein function and biogenesis, most of these efforts are being focused on sig naling receptors and large polytopic transporters because of their therapeutic potential. However, many aspects of receptor function and regulation are not completely understood and the complexity of the structure and dynamics of signaling networks in cells and tissues is only now slowly emerging, aided by complex computer-based models (Angermann et al., 2012). Within this complexity the importance of the growing cohort of small membrane proteins (SMPs), containing fewer than 100 amino acids is being recognized. Relatively few SMPs have already been characterized, but it is clear that this class of molecules carry out several important regulatory functions. SMPs have recently been demonstrated to be expressed by bacterial cells and around half of them localize to cellular membranes (Fontaine et al., 2011). Therefore, investigating the function of these proteins is currently emerging as a new and exciting field (Hobbs et al., 2011). Meanwhile, even less is known about their eukaryotic counterparts and though there are some very well characterized examples that have been known
Brought to you by | University of Connecticut Authenticated Download Date | 5/24/15 10:11 AM
1366 G. Kemp and F. Cymer: Small membrane proteins for a long time, many others have evaded detection. This is primarily because most genes that would yield protein products
Review Grant Kemp and Florian Cymer*
Small membrane proteins – elucidating the function of the needle in the haystack Abstract: Membrane proteins are important mediators between the cell and its environment or between different compartments within a cell. However, much less is known about the structure and function of membrane proteins compared to water-soluble proteins. Moreover, until recently a subset of membrane proteins, those shorter than 100 amino acids, have almost completely evaded detection as a result of technical difficulties. These small membrane proteins (SMPs) have been underrepresented in most genomic and proteomic screens of both pro- and eukaryotic cells and, hence, we know much less about their functions in both. Currently, through a combination of bioinformatics, ribosome profiling, and more sensitive proteomics, large numbers of SMPs are being identified and characterized. Herein we describe recent advances in identifying SMPs from genomic and proteomic datasets and describe examples where SMPs have been successfully characterized biochemically. Finally we give an overview of identified functions of SMPs and speculate on the possible roles SMPs play in the cell. Keywords: AcrZ; transmembrane.
KdpF;
phospholamban;
sORF;
DOI 10.1515/hsz-2014-0213 Received June 16, 2014; accepted August 6, 2014; previously published online August 12, 2014
Introduction Cellular membranes define the borders of cells. They allow the ordered intracellular space to exist next to the relatively disordered extracellular environment and separate *Corresponding author: Florian Cymer, Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden, e-mail: [email protected] Grant Kemp: Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden
the distinct microenvironments of intracellular organelles within a cell. Cellular membranes are composed of a defined lipid bilayer embedded with membrane proteins that allow the selective exchange of signals or substances between cellular compartments or the extracellular space. Indeed, the importance of membrane proteins is highlighted by the fact that nearly half of current therapeutic targets are membrane proteins (Hopkins and Groom, 2002). However, the difficulty of working with these proteins has resulted in our understanding of soluble proteins far exceeding that of membrane proteins. It is still not completely clear how membrane proteins are synthesized in a cell, how they are inserted into a membrane, how they fold and how they are eventually removed from a membrane and degraded (Brodsky, 2012; Apaja and Lukacs, 2014; Lee and Kim, 2014; Popot, 2014). Genomic screens indicate that about a quarter of all proteins in a cell are membrane proteins (Babcock and Li, 2014). While significant effort is being applied to increase our understanding of membrane protein function and biogenesis, most of these efforts are being focused on sig naling receptors and large polytopic transporters because of their therapeutic potential. However, many aspects of receptor function and regulation are not completely understood and the complexity of the structure and dynamics of signaling networks in cells and tissues is only now slowly emerging, aided by complex computer-based models (Angermann et al., 2012). Within this complexity the importance of the growing cohort of small membrane proteins (SMPs), containing fewer than 100 amino acids is being recognized. Relatively few SMPs have already been characterized, but it is clear that this class of molecules carry out several important regulatory functions. SMPs have recently been demonstrated to be expressed by bacterial cells and around half of them localize to cellular membranes (Fontaine et al., 2011). Therefore, investigating the function of these proteins is currently emerging as a new and exciting field (Hobbs et al., 2011). Meanwhile, even less is known about their eukaryotic counterparts and though there are some very well characterized examples that have been known
Brought to you by | University of Connecticut Authenticated Download Date | 5/24/15 10:11 AM
1366 G. Kemp and F. Cymer: Small membrane proteins for a long time, many others have evaded detection. This is primarily because most genes that would yield protein products
