scholarly journals To cut or not to cut: New rules for proteolytic shedding of membrane proteins

2020 ◽  
Vol 295 (35) ◽  
pp. 12353-12354
Author(s):  
Stefan F. Lichtenthaler ◽  
Edgar Meinl
Keyword(s):  
Amino Acids ◽  
Membrane Proteins ◽  
Extracellular Domain ◽  
Ectodomain Shedding ◽  
Juxtamembrane Domain ◽  
Charged Amino Acids ◽  
And Function ◽  
Proteolytic Shedding

Sheddases are specialized proteases that control the abundance and function of membrane proteins by cleaving their substrate's extracellular domain (ectodomain), a process known as shedding. Hundreds of shedding substrates have been identified, but little is known about the mechanisms that govern ectodomain shedding. Iwagishi et al. now report that negatively charged amino acids in the membrane-proximal juxtamembrane domain of substrates make them resistant to shedding by the metalloprotease ADAM17. These findings will help researchers better understand the regulation of shedding and may aid in the development of drugs targeting sheddases.

scholarly journals Negatively charged amino acids in the stalk region of membrane proteins reduce ectodomain shedding

2020 ◽  
Vol 295 (35) ◽  
pp. 12343-12352 ◽  
Author(s):  
Ryo Iwagishi ◽  
Rika Tanaka ◽  
Munenosuke Seto ◽  
Tomoyo Takagi ◽  
Naoko Norioka ◽  
...  
Keyword(s):  
Amino Acids ◽  
Membrane Proteins ◽  
Molecular Mechanisms ◽  
Alternative Exon ◽  
Ectodomain Shedding ◽  
Post Translational Modification ◽  
Charged Amino Acids ◽  
Juxtamembrane Region ◽  
Protein Variants ◽  
Variant Protein

Ectodomain shedding is a post-translational modification mechanism by which the entire extracellular domain of membrane proteins is liberated through juxtamembrane processing. Because shedding rapidly and irreversibly alters the characteristics of cells, this process is properly regulated. However, the molecular mechanisms governing the propensity of membrane proteins to shedding are largely unknown. Here, we present evidence that negatively charged amino acids within the stalk region, an unstructured juxtamembrane region at which shedding occurs, contribute to shedding susceptibility. We show that two activated leukocyte cell adhesion molecule (ALCAM) protein variants produced by alternative splicing have different susceptibilities to ADAM metallopeptidase domain 17 (ADAM17)-mediated shedding. Of note, the inclusion of a stalk region encoded by a 39-bp-long alternative exon conferred shedding resistance. We found that this alternative exon encodes a large proportion of negatively charged amino acids, which we demonstrate are indispensable for conferring the shedding resistance. We also show that the introduction of negatively charged amino acids into the stalk region of shedding-susceptible ALCAM variant protein attenuates its shedding. Furthermore, we observed that negatively charged amino acids residing in the stalk region of Erb-B2 receptor tyrosine kinase 4 (ERBB4) are indispensable for its shedding resistance. Collectively, our results indicate that negatively charged amino acids within the stalk region interfere with the shedding of multiple membrane proteins. We conclude that the composition of the stalk region determines the shedding susceptibility of membrane proteins.

Small membrane proteins – elucidating the function of the needle in the haystack

2014 ◽  
Vol 395 (12) ◽  
pp. 1365-1377 ◽  
Author(s):  
Grant Kemp ◽  
Florian Cymer
Keyword(s):  
Amino Acids ◽  
Membrane Proteins ◽  
Soluble Proteins ◽  
Structure And Function ◽  
Ribosome Profiling ◽  
Water Soluble ◽  
Eukaryotic Cells ◽  
Large Numbers ◽  
A Cell ◽  
And Function

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.

scholarly journals A unifying mechanism for the biogenesis of prokaryotic membrane proteins co-operatively integrated by the Sec and Tat pathways

2017 ◽  
Author(s):  
Fiona J. Tooke ◽  
Marion Babot ◽  
Govind Chandra ◽  
Grant Buchanan ◽  
Tracy Palmer
Keyword(s):  
Amino Acids ◽  
Membrane Proteins ◽  
Streptomyces Coelicolor ◽  
Bioinformatic Analysis ◽  
Protein Families ◽  
Iron Sulfur Cluster ◽  
Sec Pathway ◽  
Charged Amino Acids ◽  
Loop Region ◽  
Twin Arginine Translocase

AbstractThe vast majority of polytopic membrane proteins are inserted into the cytoplasmic membrane of prokaryotes by the general secretory (Sec) pathway. However, a subset of monotopic proteins that contain non-covalently-bound redox cofactors depend on the twin-arginine translocase (Tat) machinery for membrane integration. Recently actinobacterial Rieske iron-sulfur cluster-containing proteins were identified as an unusual class of membrane proteins that require both the Sec and Tat pathways for the insertion of their three transmembrane domains (TMDs). The Sec pathway inserts the first two TMDs of these proteins co-translationally, but releases the polypeptide prior to the integration of TMD3 to allow folding of the cofactor-containing domain and its translocation by Tat. Here we have investigated features of the Streptomyces coelicolor Rieske polypeptide that modulate its interaction with the Sec and Tat machineries. Mutagenesis of a highly conserved loop region between Sec-dependent TMD2 and Tat-dependent TMD3 shows that it plays no significant role in coordinating the activities of the two translocases, but that a minimum loop length of approximately eight amino acids is required for the Tat machinery to recognise TMD3. Instead we show that a combination of relatively low hydrophobicity of TMD3, coupled with the presence of C-terminal positively-charged amino acids, results in abortive insertion of TMD3 by the Sec pathway and its release at the cytoplasmic side of the membrane. Bioinformatic analysis identified two further families of polytopic membrane proteins that share features of dual Sec-Tat-targeted membrane proteins. A predicted heme-molybdenum cofactor-containing protein with five TMDs, and a polyferredoxin also with five predicted TMDs, are encoded across bacterial and archaeal genomes. We demonstrate that membrane insertion of representatives of each of these newly-identified protein families is dependent on more than one protein translocase, with the Tat machinery recognising TMD5. Importantly, the combination of low hydrophobicity of the final TMD and the presence of multiple C-terminal positive charges that serve as critical Sec-release features for the actinobacterial Rieske protein also dictate Sec release in these further protein families. Therefore we conclude that a simple unifying mechanism governs the assembly of dual targeted membrane proteins.

How Do Lipids Affect the Structure and Function of Integral Membrane Proteins

2012 ◽  
Vol 28 (11) ◽  
pp. 866
Author(s):  
Jie HENG ◽  
Yan WU ◽  
Xianping WANG ◽  
Kai ZHANG
Keyword(s):  
Membrane Proteins ◽  
Structure And Function ◽  
Integral Membrane Proteins ◽  
And Function

Gill microbiome structure and function in the chemosymbiotic coastal lucinid Stewartia floridana

2021 ◽  
Author(s):  
Shen Jean Lim ◽  
Brenton Davis ◽  
Danielle Gill ◽  
John Swetenburg ◽  
Laurie C Anderson ◽  
...  
Keyword(s):  
Amino Acids ◽  
Nutrient Cycling ◽  
Bacterial Communities ◽  
Structure And Function ◽  
Differentially Expressed ◽  
Seagrass Species ◽  
Bare Sand ◽  
And Function

Abstract Lucinid bivalves harbor environmentally acquired, chemosynthetic, gammaproteobacterial gill endosymbionts. Lucinid gill microbiomes, which may contain other gammaproteobacterial and/or spirochete taxa, remain under-sampled. To understand inter-host variability of the lucinid gill microbiome, specifically in the bacterial communities, we analyzed the microbiome content of Stewartia floridana collected from Florida. Sampled gills contained a monospecific gammaproteobacterial endosymbiont expressing lithoautotrophic, mixotrophic, diazotrophic, and C1 compound oxidation-related functions previously characterized in similar lucinid species. Another low-abundance Spirochaeta-like species in ∼72% of the sampled gills was most closely related to Spirochaeta-like species in another lucinid Phacoides pectinatus and formed a clade with known marine Spirochaeta symbionts. The spirochete expressed genes were involved in heterotrophy and the transport of sugars, amino acids, peptides, and other substrates. Few muscular and neurofilament genes from the host and none from the gammaproteobacterial and spirochete symbionts were differentially expressed among quadrats predominantly covered with seagrass species or 80% bare sand. Our results suggest that spirochetes are facultatively associated with S. floridana, with potential scavenging and nutrient cycling roles. Expressed stress- and defense-related functions in the host and symbionts also suggest species-species communications, which highlight the need for further study of the interactions among lucinid hosts, their microbiomes, and their environment.

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