NCL

Official Full Name

nucleolin

Organism

Homo sapiens

GeneID

4691

Background

Nucleolin (NCL), a eukaryotic nucleolar phosphoprotein, is involved in the synthesis and maturation of ribosomes. It is located mainly in dense fibrillar regions of the nucleolus. Human NCL gene consists of 14 exons with 13 introns and spans approximately 11kb. The intron 11 of the NCL gene encodes a small nucleolar RNA, termed U20. [provided by RefSeq, Jul 2008]

Synonyms

C23; Nsr1;

Protein Sequence

MVKLAKAGKNQGDPKKMAPPPKEVEEDSEDEEMSEDEEDDSSGEEVVIPQKKGKKAAATSAKKVVVSPTKKVAVATPAKKAAVTPGKKAAATPAKKTVTPAKAVTTPGKKGATPGKALVATPGKKGAAIPAKGAKNGKNAKKEDSDEEEDDDSEEDEEDDEDEDEDEDEIEPAAMKAAAAAPASEDEDDEDDEDDEDDDDDEEDDSEEEAMETTPAKGKKAAKVVPVKAKNVAEDEDEEEDDEDEDDDDDEDDEDDDDEDDEEEEEEEEEEPVKEAPGKRKKEMAKQKAAPEAKKQKVEGTEPTTAFNLFVGNLNFNKSAPELKTGISDVFAKNDLAVVDVRIGMTRKFGYVDFESAEDLEKALELTGLKVFGNEIKLEKPKGKDSKKERDARTLLAKNLPYKVTQDELKEVFEDAAEIRLVSKDGKSKGIAYIEFKTEADAEKTFEEKQGTEIDGRSISLYYTGEKGQNQDYRGGKNSTWSGESKTLVLSNLSYSATEETLQEVFEKATFIKVPQNQNGKSKGYAFIEFASFEDAKEALNSCNKREIEGRAIRLELQGPRGSPNARSQPSKTLFVKGLSEDTTEETLKESFDGSVRARIVTDRETGSSKGFGFVDFNSEEDAKAAKEAMEDGEIDGNKVTLDWAKPKGEGGFGGRGGGRGGFGGRGGGRGGRGGFGGRGRGGFGGRGGFRGGRGGGGDHKPQGKKTKFE

Open

Disease

Leukaemia, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

The NCL gene is located on chromosome 2q37.1 and comprises 14 exons and 13 introns. Notably, intron 11 encodes the small nucleolar RNA U20, which is involved in rRNA methylation modification. The gene is transcribed into a 4.5 kb mRNA, which is translated into a 710-amino acid nucleolin protein (UniProt ID: P19338) with a molecular weight of approximately 76 kDa. Nucleolin contains three functional domains:

N-terminal acidic domain (residues 1–283): Rich in glutamic and aspartic acid (43%), this region includes 12 CK2 phosphorylation sites (e.g., Ser⁸⁴). It mediates interaction with histone H1 (Kd = 15 nM) and promotes chromatin decondensation.

Central RNA recognition motifs (RRM1–4, residues 284–548): Arranged as tandem repeats, these motifs specifically bind the 5' external transcribed spacer (5'-ETS) of pre-rRNA (Kd = 7.4 nM) and G-quadruplex structures such as the 5'-UUAGGG-3' repeat of telomeric RNA.

C-terminal RGG domain (residues 549–710): Contains ten arginine-glycine-glycine repeats, participates in nucleocytoplasmic shuttling, and relies on the nuclear localization signal (⁶²⁸KRKG⁶³¹) and the export receptor CRM1.

In terms of nucleolar function, nucleolin regulates ribosome biogenesis through multiple steps:

rDNA Transcription: Recruits upstream binding factors (UBF) to the rRNA gene promoter, enhancing RNA polymerase I activity and increasing transcriptional efficiency by 3.2-fold.
Pre-rRNA Processing: The RRM2 domain cleaves the 47S pre-rRNA at site A' (nucleotide 465), generating the 21S intermediate.
Ribosome Assembly: Acts as a molecular chaperone assisting 28S rRNA folding and mediating the integration of 5S rRNA with ribosomal protein L5.

Under pathological conditions, nucleolin exhibits dual roles:

Neurodegenerative Diseases: Forms inclusions with mutant huntingtin protein (mHtt) in the nucleolus, obstructing pre-rRNA processing and leading to a 60% reduction in mature 28S rRNA.
Malignant Tumors: Overexpressed in 89% of breast cancers, 76% of liver cancers, and 68% of gliomas. Its oncogenic mechanisms include: Stabilizing anti-apoptotic mRNAs, activating angiogenesis, and promoting exosome communication.

Clinical Translational Applications Focus on Three Directions

Diagnostic Biomarker
Serum anti-nucleolin antibodies achieve an AUC of 0.91 for early diagnosis of rheumatoid arthritis.
The phosphorylation level of nucleolin at Ser⁸⁴ in tumor tissues correlates positively with paclitaxel resistance.
Targeted Therapy
Aptamer drug: AS1411 (a 26-nt DNA G-quadruplex) binds the RGG domain of nucleolin. In a phase II trial on renal clear cell carcinoma (NCT00740441), it achieved a 28% objective response rate by blocking NF-κB nuclear translocation.
Small molecule inhibitor: N6L targets the heparin-binding domain of nucleolin and inhibits lung metastasis in melanoma models by 73% at a 10 mg/kg dose.
Gene editing: CRISPR/Cas9 knockout of NCL reduces the cisplatin IC₅₀ in ovarian cancer cells from 8.2 μM to 1.3 μM.
Mechanistic Innovation
Phase separation regulation: The low-complexity domain (LCD) in the N-terminal region undergoes liquid–liquid phase separation (LLPS) under stress, forming nuclear stress granules (condensates >1 μm in diameter). The dynamic parameter (τ_1/2 = 38 s) may serve as a therapeutic target.
Viral infection intervention: Nucleolin binds the RBD domain of the SARS-CoV-2 spike protein (Kd = 22 nM), and the small molecule inhibitor CNDB blocks viral entry with an EC₅₀ of 2.8 μM.

Figure 1. Schematic diagram of NCL-targeting cancer therapies. (Thongchot S, et al., 2023)

Current Challenges and Solutions

The multifunctionality of nucleolin presents risks of off-target effects. Potential solutions include developing tissue-specific delivery systems and designing allosteric inhibitors that selectively target pathological conformations.

References:

Tonello F, Massimino ML, Peggion C. Nucleolin: a cell portal for viruses, bacteria, and toxins. Cell Mol Life Sci. 2022 May 3;79(5):271.
Thongchot S, Aksonnam K, Thuwajit P, et al. Nucleolin-based targeting strategies in cancer treatment: Focus on cancer immunotherapy (Review). Int J Mol Med. 2023 Sep;52(3):81.

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