The organelle proteome

Spatial compartmentalization of biological functions is a fundamental strategy that enables multiple biological processes to occur in parallel without undesired interference. An organelle is a subunit of the eukaryotic cell with a specialized function. The name "organelle" stems from the analogy between the different roles of organelles in the cells to the different roles of organs in the human body as a whole. A distinction is often made between membrane-bound and non-membrane bound organelles. The membrane-bound organelles, such as the nucleus and the Golgi apparatus, have a clearly defined physical boundary that separates the internal space from the outside. In contrast, non-membrane bound organelles and subcellular compartments, like the cytoskeleton and nucleoli, constitute spatially distinct assemblies of proteins, and sometimes RNA, within the cell without a physical boundary. This partitioning of cellular components creates specific environments where the concentration of different molecules can be tailored to fit the purpose of the organelle or subcellular structure, and provides important opportunities for regulation and coordination of cellular processes.

A major function of proteins is to catalyze, conduct and control cellular processes in time and space. As different organelles and subcellular structures offer distinct environments, with distinct physiological conditions and interaction partners, the subcellular localization of a protein is an important factor for protein function. Consequently, mis-localization of proteins is associated with cellular dysfunction and various human diseases (Kau TR et al. (2004); Laurila K et al. (2009); Park S et al. (2011)). Knowledge of the spatial distribution of proteins at the subcellular level is essential for understanding protein function and molecular interactions, as well as for identifying the components of different cellular processes. Thus, studying how cells generate and maintain their spatial organization is central for understanding the mechanisms of living cells.

Within the subcellular section, 13105 human proteins have been mapped at single-cell level to 35 different organelles and subcellular structures (Figure 1), which has enabled the definition of 13 major organelle proteomes:

The analysis also reveals that approximately half of the proteins localize to multiple compartments and identifies many proteins with single-cell variation in terms of protein abundance and/or spatial distribution.

Subcellular localization of proteins

Several approaches for systematic analysis of protein localization have been described. The first major approach is organelle fractionation and quantitative mass-spectrometry, which can allow identification of the subcellular location of proteins by comparing their distribution profiles across the fractions with known organelle markers (Park S et al. (2011); Christoforou A et al. (2016); Itzhak DN et al. (2016)). The second major approach is to use protein-protein interaction studies to deduce the local spatial proteome of proteins. In this case, affinity purification or enzyme-mediated proximity-labelling, cis used to deduce unknown protein subcellular locations from interaction networks overlayed with known subcellular locazations (Itzhak DN et al. (2016); Roux KJ et al. (2012); Lee SY et al. (2016)). The third major approach is imaging-based methods, which enable the exploration of subcellular distribution of proteins in situ in single cells. These approaches are complemental, but imaging -based subcular profiling has the advantage of effectively identifying single-cell variability and multi-organelle localization. Imaging based approaches can be performed using tagged recombinant proteins (Huh WK et al. (2003); Simpson JC et al. (2000); Stadler C et al. (2013)) or affinity reagents, such as antibodies.

The subcellular section employs an immunofluorescence (IF) based approach combined with confocal microscopy to enable high-resolution investigation of the spatial distribution of proteins in fixed c (Thul PJ et al. (2017); Stadler C et al. (2013); Barbe L et al. (2008); Stadler C et al. (2010); Fagerberg L et al. (2011)). With the diffraction-limited resolution of about 200 nm, a confocal image gives detailed insights into organization at the subcullar level. The spatial distribution of the protein is investigated using indirect IF in up to three cell lines, usually including U-2 OS and two additional cell lines selected based on mRNA expression of the corresponding gene, using a subset of 37 of the cell lines found in the cell line section of the Human Protein Atlas. The protein of interest is visualized in green, while reference markers for microtubules (red), endoplasmic reticulum (yellow) and nucleus (blue) are used to outline the cell. From small dots like nuclear bodies, to larger structures such as the nucleoplasm, the distinct patterns in the images together with the reference markers make it possible to precisely determine the spatial distribution of a protein within the cell. The localization of each protein is assigned to one or more of 35 organelles and subcellular structures (Figure 1).


Nucleoplasm

Nuclear speckles

Nuclear bodies

Nucleoli

Nucleoli fibrillar center

Nucleoli rim

Mitotic chromosome

Kinetochore

Nuclear membrane

Cytosol

Cytoplasmic bodies

Rods & Rings

Aggresome

Mitochondria

Centrosome

Centriolar satellites

Microtubules

Microtubule ends

Mitotic spindle

Cytokinetic bridge

Midbody

Midbody ring

Cleavage furrow

Intermediate filaments

Actin filaments

Focal adhesion sites

Endoplasmic reticulum

Golgi apparatus

Vesicles

Endosomes

Lysosomes

Lipid droplets

Peroxisomes

Plasma membrane

Cell junctions

Figure 1. An example of confocal immunofluorescence images of different proteins (green) localized to each of the subcellular organelles and substructures currently annotated in the subcellular section in a representative set of cell lines. Microtubules are marked with an anti-tubulin antibody (red) and the nucleus is counterstained with DAPI (blue). For more example images and details describing all the 35 patterns annotated in the subcellular section, see the Cell structure dictionary.

Protein distribution in human cells

Figure 2 shows the distribution of all classificactions across the 35 organelles and subcellular structures for 13105 genes with protein localization data in the subcellular section. The plot is sorted by meta-compartments: cytoplasm, nucleus, and endomembrane system, respectively. Most proteins are found in the nucleus, followed by the cytosol and vesicles, which consist of transport vesicles as well as small membrane-bound organelles like endosomes or peroxisomes. 57% (n=7413) of the proteins were detected in more than one location (multilocalizing proteins), and 24% (n=3185) displayed single-cell variation in expression level or spatial distribution.

Figure 2. Bar plot showing the distribution of classifications of proteins in organelles and subcellular structures in the Subcellular Section. Note that one protein can localize to more than one compartment. The bars are colored according to meta compartment.

Validation of antibodies and location data for the Subcellular Section

The quality and use of antibodies in research have been frequently debated (Baker M. (2015)). As antibody off-target binding can cause false positive results, the subcellular section makes an effort in manually scoring all results in terms of reliability. In the subcellular section a reliability score for every annotated location at a four-graded scale is provided: Enhanced, Supported, Approved, and Uncertain, as described in detail in the assay & annotation section. The Enhanced locations are obtained through antibody validation according to one of the validation "pillars" proposed by an international working group (Uhlen M et al. (2016): (i) genetic methods using siRNA silencing (Stadler C et al. (2012)) or CRISPR/Cas9 knock-out, (ii) expression of a fluorescent protein-tagged protein at endogenous levels (Skogs M et al. (2017)) or (iii) independent antibodies targeting different epitopes (Stadler C et al. (2010)). A Supportive location is in agreement with external experimental data (UniProt database), while an Approved location score indicates that there is no external experimental information available to confirm the observed location or that external data is only partially supportive. An Uncertain location is contradictory compared to external protein localization data or protein function, but is shown if it cannot be ruled out that the data is correct, and further experiments are needed to establish the reliability of the antibody staining. The individual location reliability scores are summarized into an overall gene reliability score. The distribution of reliability scores in the subcellular section is shown in Figure 3. Approximately 43% (n=5654) of the protein localizations provided are enhanced or supported. Table 1 details the organelle distribution of all localized proteins and the distribution of reliability scores on the basis of the individual organelle.

Figure 3. Pie chart showing level of reliability of the localized proteins, where each piece is the number of proteins with one type of score, out of the four reliability scores Enhanced, Supported, Approved, and Uncertain.

Table 1. Table showing the number of proteins localized to every organelle, structure, and substructure in the subcellular section, along with the distribution of reliability scores.

Location Proteins Location reliability
% Enhanced Supported Approved Uncertain
Intermediate filaments 1671.3131710532
Actin filaments 2391.8153814343
Focal adhesion sites 1391.111267824
Microtubules 2762.164817250
Microtubule ends 600321
Cytokinetic bridge 1581.232510426
Midbody 550.4412327
Midbody ring 260.212185
Cleavage furrow 100010
Mitotic spindle 930.72294814
Centriolar satellite 1881.4123610535
Centrosome 3993118824951
Mitochondria 11198.512239052483
Aggresome 190.100154
Cytosol 486337.132014242592527
Cytoplasmic bodies 730.6325378
Rods & Rings 190.103142
Endoplasmic reticulum 5394.15119426727
Golgi apparatus 11538.869203753128
Vesicles 222817943651453316
Peroxisomes 230.261151
Endosomes 170.151020
Lysosomes 190.111620
Lipid droplets 390.3611211
Plasma membrane 204415.61116441064225
Cell Junctions 3252.5229318129
Nucleoplasm 614646.972018522973601
Nuclear membrane 2802.1156417724
Nucleoli 10768.296259563158
Nucleoli fibrillar center 3102.4137519725
Nucleoli rim 1531.232486211
Nuclear speckles 4903.75015624044
Nuclear bodies 5874.54120429349
Kinetochore 600510
Mitotic chromosome 740.61516385
Number of proteins 131051001440480975491840

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