Predicting the targeting of tail-anchored proteins to subcellular compartments in mammalian cells.
Tail-anchored (TA) proteins contain a single transmembrane domain (TMD) at the C-terminus that anchors them to the membranes of organelles where they mediate critical cellular processes. Accordingly, mutations in genes encoding TA proteins have been identified in a number of severe inherited disorders. Despite the importance of correctly targeting a TA protein to its appropriate membrane, the mechanisms and signals involved are not fully understood. In this study, we identify additional peroxisomal TA proteins, discover more proteins that are present on multiple organelles, and reveal that a combination of TMD hydrophobicity and tail charge determines targeting to distinct organelle locations in mammals. Specifically, an increase in tail charge can override a hydrophobic TMD signal and re-direct a protein from the ER to peroxisomes or mitochondria and vice versa. We show that subtle changes in those parameters can shift TA proteins between organelles, explaining why peroxisomes and mitochondria have many of the same TA proteins. This enabled us to associate characteristic physicochemical parameters in TA proteins with particular organelle groups. Using this classification allowed successful prediction of the location of uncharacterized TA proteins for the first time.
Biosciences, University of Exeter, Exeter EX4 4QD, UK.
Joseph L
JL
Costello
Biosciences, University of Exeter, Exeter EX4 4QD, UK.
Inês G
IG
Castro
Centre for Cell Biology/Institute of Biomedicine & Department of Biology, University of Aveiro, Aveiro 3810-193, Portugal.
Fátima
F
Camões
Biosciences, University of Exeter, Exeter EX4 4QD, UK.
Tina A
TA
Schrader
Met Office Hadley Centre, Exeter EX1 3PB, UK.
Doug
D
McNeall
Temasek Life Sciences Laboratory, Department of Biological Sciences, National University of Singapore, Singapore.
Jing
J
Yang
EMBL Hamburg, c/o DESY, Hamburg 22603, Germany.
Evdokia-Anastasia
EA
Giannopoulou
Centre for Cell Biology/Institute of Biomedicine & Department of Biology, University of Aveiro, Aveiro 3810-193, Portugal.
Sílvia
0000-0001-8473-4420
S
Gomes
EMBL Hamburg, c/o DESY, Hamburg 22603, Germany.
Vivian
V
Pogenberg
Centre for Cell Biology/Institute of Biomedicine & Department of Biology, University of Aveiro, Aveiro 3810-193, Portugal.
Nina A
NA
Bonekamp
Centre for Cell Biology/Institute of Biomedicine & Department of Biology, University of Aveiro, Aveiro 3810-193, Portugal.
Daniela
D
Ribeiro
EMBL Hamburg, c/o DESY, Hamburg 22603, Germany.
Matthias
M
Wilmanns
Temasek Life Sciences Laboratory, Department of Biological Sciences, National University of Singapore, Singapore.
Gregory
G
Jedd
Institute of Neuroanatomy, Center for Biomedicine and Medical Technology Mannheim, University of Heidelberg, Mannheim 68167, Germany Markus.Islinger@medma.uni-heidelberg.de M.Schrader@exeter.ac.uk.
Markus
M
Islinger
Biosciences, University of Exeter, Exeter EX4 4QD, UK Markus.Islinger@medma.uni-heidelberg.de M.Schrader@exeter.ac.uk.|Centre for Cell Biology/Institute of Biomedicine & Department of Biology, University of Aveiro, Aveiro 3810-193, Portugal.
Michael
0000-0003-2146-0535
M
Schrader
D000818:Animals; D002451:Cell Compartmentation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007425:Intracellular Membranes / Q000378:metabolism; D008322:Mammals / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D020675:Peroxisomes / Q000378:metabolism; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism
D008565:Membrane Proteins
ACBD5; Mitochondria; Peroxisomes; Tail-anchored protein