Page last updated: 2024-10-24

protein targeting to lysosome

Definition

Target type: biologicalprocess

The process of directing proteins towards the lysosome using signals contained within the protein. [GOC:curators]

Protein targeting to lysosomes is a complex and highly regulated process essential for maintaining cellular homeostasis. It involves the delivery of proteins, including soluble enzymes, transmembrane proteins, and receptors, from the trans-Golgi network (TGN) to the lysosome, where they are degraded or sorted for other cellular destinations. The process relies on a series of molecular signals embedded within the target proteins and the intricate machinery of the secretory pathway.

The journey begins with the synthesis of proteins destined for the lysosome on ribosomes attached to the endoplasmic reticulum (ER). These proteins typically possess a unique sorting signal known as a lysosomal targeting signal (LTS), which directs them to the lysosomal pathway. Several types of LTS have been identified, including:

1. **Mannose-6-phosphate (M6P) residues:** The most common and well-characterized LTS. M6P residues are added to lysosomal hydrolases in the Golgi apparatus, specifically in the cis-Golgi, through a series of enzymatic reactions. These residues are recognized by M6P receptors present on the TGN membrane.

2. **Other signals:** While M6P-mediated sorting is the dominant mechanism, other signals, including dileucine motifs, tyrosine-based signals, and GPI anchors, have also been identified and contribute to lysosomal targeting.

Once the proteins reach the TGN, they interact with the M6P receptors, initiating their journey to the lysosome. The M6P receptor-ligand complex moves through the TGN and is packaged into clathrin-coated vesicles. These vesicles bud off from the TGN and fuse with late endosomes, acidic compartments that serve as intermediates in the lysosomal pathway.

Inside the late endosomes, the acidic environment triggers the dissociation of the M6P receptor from the lysosomal hydrolases. The receptors cycle back to the TGN for further rounds of cargo transport, while the lysosomal enzymes are retained within the late endosomes.

Finally, the late endosomes mature into lysosomes, acidic organelles containing a diverse array of hydrolytic enzymes capable of degrading various cellular components, including proteins, lipids, and carbohydrates.

This intricate targeting process ensures the efficient delivery of lysosomal enzymes to their designated destination, enabling the lysosome to perform its critical role in cellular recycling and degradation. Defects in this pathway can lead to various lysosomal storage disorders, highlighting the importance of precise protein sorting for maintaining cellular homeostasis and preventing disease.'
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Proteins (6)

ProteinDefinitionTaxonomy
N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidaseAn N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9UK23]Homo sapiens (human)
SortilinA sortilin that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q99523]Homo sapiens (human)
Phosphatidylinositol 3-kinase catalytic subunit type 3A phosphatidylinositol 3-kinase catalytic subunit type 3 that is encoded in the genome of human. [PRO:DNx]Homo sapiens (human)
Nuclear receptor coactivator 4A nuclear receptor coactivator 4 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q13772]Homo sapiens (human)
Ras-related protein Rab-7aA Ras-related protein Rab-7a that is encoded in the genome of human. [PRO:DNx, UniProtKB:P51149]Homo sapiens (human)
Lutropin-choriogonadotropic hormone receptorA lutropin-choriogonadotropic hormone receptor that is encoded in the genome of human. [PRO:WCB, UniProtKB:P22888]Homo sapiens (human)

Compounds (33)

CompoundDefinitionClassesRoles
sr 48692SR 48692: structure in first source; a neurotensin receptor-1 antagonistN-acyl-amino acid
2-[[benzamido(sulfanylidene)methyl]amino]-5,5-dimethyl-4,7-dihydrothieno[2,3-c]pyran-3-carboxylic acidCID1067700: a pan-GTPase inhibitor; structure in first sourcethienopyran
ML162ML162 : A monochlorobenzene that is benzene substituted by (chloroacetyl){2-oxo-2-[(2-phenylethyl)amino]-1-(thiophen-2-yl)ethyl}amino, chloro and methoxy groups at positions 1, 3 and 4, respectively. It is a covalent inhibitor of glutathione peroxidase 4 (GPX4) that induces ferroptosis in cells.monochlorobenzenes;
monomethoxybenzene;
organochlorine compound;
secondary carboxamide;
tertiary carboxamide;
thiophenes
EC 1.11.1.9 (glutathione peroxidase) inhibitor;
ferroptosis inducer
n-acetylglucosaminono-1,5-lactone o-(phenylcarbamoyl)oximeN-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime: structure given in first source
lenvatiniblenvatinib : A member of the class of quinolines that is the carboxamide of 4-{3-chloro-4-[(cyclopropylcarbamoyl)amino]phenoxy}-7-methoxyquinoline-6-carboxylic acid. A multi-kinase inhibitor and orphan drug used (as its mesylate salt) for the treatment of various types of thyroid cancer that do not respond to radioiodine.aromatic amide;
aromatic ether;
cyclopropanes;
monocarboxylic acid amide;
monochlorobenzenes;
phenylureas;
quinolines
antineoplastic agent;
EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor;
fibroblast growth factor receptor antagonist;
orphan drug;
vascular endothelial growth factor receptor antagonist
org 41841Org 41841: structure in first sourcepyrimidines;
thienopyrimidine
PI3-Kinase alpha Inhibitor 2organic heterobicyclic compound;
organonitrogen heterocyclic compound;
organosulfur heterocyclic compound
idelalisibidelalisib : A member of the class of quinazolines that is 5-fluoro-3-phenylquinazolin-4-one in which the hydrogen at position 2 is replaced by a (1S)-1-(3H-purin-6-ylamino)propyl group. used for for the treatment of refractory indolent non-Hodgkin's lymphoma and relapsed chronic lymphocytic leukemia.

idelalisib: an antineoplastic agent and p110delta inhibitor; structure in first source
aromatic amine;
organofluorine compound;
purines;
quinazolines;
secondary amino compound
antineoplastic agent;
apoptosis inducer;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor
zstk474ZSTK-474 : A triamino-1,3,5-triazine that is 1,3,5-triazine in which two of the hydrogens have been replaced by morpholin-4-yl groups while the third hydrogen has been replaced by a 2-(difluoromethyl)benzimidazol-1-yl group. It is an inhibitor of phosphatidylinositol 3-kinase.benzimidazoles;
morpholines;
organofluorine compound;
triamino-1,3,5-triazine
antineoplastic agent;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor
dactolisibdactolisib : An imidazoquinoline that is 3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinoline substituted at position 1 by a 4-(1-cyanoisopropyl)phenyl group and at position 8 by a quinolin-3-yl group. A dual PI3K/mTOR inhibitor used in cancer treatment.

dactolisib: antineoplastic agent that inhibits both phosphatidylinositol 3-kinase and mTOR
imidazoquinoline;
nitrile;
quinolines;
ring assembly;
ureas
antineoplastic agent;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor;
mTOR inhibitor
ku 60019
buparlisibNVP-BKM120: a pan class I PI3 kinase inhibitor with antineoplastic activity; structure in first sourceaminopyridine;
aminopyrimidine;
morpholines;
organofluorine compound
antineoplastic agent;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor
gdc 0941pictrelisib : A sulfonamide composed of indazole, morpholine, and methylsulfonyl-substituted piperazine rings bound to a thienopyrimidine ring.indazoles;
morpholines;
piperazines;
sulfonamide;
thienopyrimidine
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor
neurotensinneurotensin, Tyr(11)-: RN given refers to parent cpd & (D)-isomer; RN for cpd without isomeric designation not avail 5/91peptide hormonehuman metabolite;
mitogen;
neurotransmitter;
vulnerary
gdc 0980
azd2014vistusertib: potent and selective dual mTORC1 and mTORC2 inhibitor; structure in first source
pki 587gedatolisib: inhibits both phosphatidylinositol 3-kinase and mTOR; structure in first source
5-(4-amino-1-propan-2-yl-3-pyrazolo[3,4-d]pyrimidinyl)-1,3-benzoxazol-2-aminesapanisertib: an mTOR inhibitorbenzoxazole
ch 5132799CH 5132799: structure in first source
torin 1torin 1 : A member of the class of pyridoquinolines that is 9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2-one bearing an additional 4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl substituent at position 1. It is a potent inhibitor of mTOR and exhibits anti-cancer properties.N-acylpiperazine;
N-arylpiperazine;
organofluorine compound;
pyridoquinoline;
quinolines
antineoplastic agent;
mTOR inhibitor
gdc-0032
spautin-1
torin 2torin 2 : A member of the class of pyridoquinolines that is benzo[h][1,6]naphthyridin-2-one carrying additional 3-(trifluoromethyl)phenyl and 6-aminopyridin-3-yl substituents at positions 1 and 9 respectively. It is a potent inhibitor of mTOR and exhibits anti-cancer properties.aminopyridine;
organofluorine compound;
primary amino compound;
pyridoquinoline
antineoplastic agent;
mTOR inhibitor
cudc-907
sar245408
byl719proline derivative
cep-32496agerafenib: inhibitor of RAF family kinases; structure in first source
amg 511AMG 511: structure in first source
cc-223
af38469
sar405SAR405: a Vps34 inhibitor with antineoplastic activity; structure in first source
guanosine diphosphateGuanosine Diphosphate: A guanine nucleotide containing two phosphate groups esterified to the sugar moiety.guanosine 5'-phosphate;
purine ribonucleoside 5'-diphosphate
Escherichia coli metabolite;
mouse metabolite;
uncoupling protein inhibitor
guanosine triphosphateGuanosine Triphosphate: Guanosine 5'-(tetrahydrogen triphosphate). A guanine nucleotide containing three phosphate groups esterified to the sugar moiety.guanosine 5'-phosphate;
purine ribonucleoside 5'-triphosphate
Escherichia coli metabolite;
mouse metabolite;
uncoupling protein inhibitor