Target Information

Target General Information

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Target ID

T95742 (Former ID: TTDR00725)

Target Name

Neurofibromin-2 (NF2)

Synonyms

Schwannomin; Schwannomerlin; SCH; Moesin-ezrin-radixin-like protein; Merlin

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Gene Name

NF2

Target Type

Literature-reported target

[1]

Function

Probable regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in tumor suppression by restricting proliferation and promoting apoptosis. Along with WWC1 can synergistically induce the phosphorylation of LATS1 and LATS2 and can probably function in the regulation of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway. May act as a membrane stabilizing protein. May inhibit PI3 kinase by binding to AGAP2 and impairing its stimulating activity. Suppresses cell proliferation and tumorigenesis by inhibiting the CUL4A-RBX1-DDB1-VprBP/DCAF1 E3 ubiquitin-protein ligase complex.

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UniProt ID

MERL_HUMAN

Sequence

MAGAIASRMSFSSLKRKQPKTFTVRIVTMDAEMEFNCEMKWKGKDLFDLVCRTLGLRETW
FFGLQYTIKDTVAWLKMDKKVLDHDVSKEEPVTFHFLAKFYPENAEEELVQEITQHLFFL
QVKKQILDEKIYCPPEASVLLASYAVQAKYGDYDPSVHKRGFLAQEELLPKRVINLYQMT
PEMWEERITAWYAEHRGRARDEAEMEYLKIAQDLEMYGVNYFAIRNKKGTELLLGVDALG
LHIYDPENRLTPKISFPWNEIRNISYSDKEFTIKPLDKKIDVFKFNSSKLRVNKLILQLC
IGNHDLFMRRRKADSLEVQQMKAQAREEKARKQMERQRLAREKQMREEAERTRDELERRL
LQMKEEATMANEALMRSEETADLLAEKAQITEEEAKLLAQKAAEAEQEMQRIKATAIRTE
EEKRLMEQKVLEAEVLALKMAEESERRAKEADQLKQDLQEAREAERRAKQKLLEIATKPT
YPPMNPIPAPLPPDIPSFNLIGDSLSFDFKDTDMKRLSMEIEKEKVEYMEKSKHLQEQLN
ELKTEIEALKLKERETALDILHNENSDRGGSSKHNTIKKLTLQSAKSRVAFFEEL

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3D Structure

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AlphaFold

HIT2.0 ID

T50HUJ

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: [(2r)-2-Octanoyloxy-3-[oxidanyl-[(1r,2r,3s,4r,5r,6s)-2,3,6-Tris(Oxidanyl)-4,5-Diphosphonooxy-Cyclohexyl]oxy-Phosphoryl]oxy-Propyl] Octanoate

Ligand Info

Structure Description

Human neurofibromin 2/merlin/schwannomin residues 1-339 in complex with PIP2

PDB:6CDS

Method

X-ray diffraction

Resolution

2.62 Å

Mutation

Yes

[2]

PDB Sequence

KRKQPKTFTV

²⁴

RIVTMDAEME

³⁴

FNCEMKWKGK

⁴⁴

DLFDLVCRTL

⁵⁴

GLRETWFFGL

⁶⁴

QYTIKDTVAW

⁷⁴

LKMDKKVLDH

⁸⁴

DVSKEEPVTF

⁹⁴

HFLAKFYPEN

¹⁰⁴

AEEELVQEIT

¹¹⁴

QHLFFLQVKK

¹²⁴

QILDEKIYCP

¹³⁴

PEASVLLASY

¹⁴⁴

AVQAKYGDYD

¹⁵⁴

PSVHKRGFLA

¹⁶⁴

QEELLPKRVI

¹⁷⁴

NLYQMTPEMW

¹⁸⁴

EERITAWYAE

¹⁹⁴

HRGRARDEAE

²⁰⁴

MEYLKIAQDL

²¹⁴

EMYGVNYFAI

²²⁴

RNKKGTELLL

²³⁴

GVDALGLHIY

²⁴⁴

DPENRLTPKI

²⁵⁴

SFPWNEIRNI

²⁶⁴

SYSDKEFTIK

²⁷⁴

PLDKKIDVFK

²⁸⁴

FNSSKLRVNK

²⁹⁴

LILQLCIENH

³⁰⁴

DLFMRRRKAD

³¹⁴

SLEVQQMKAQ

³²⁴

AREEKARKQM

³³⁴

ERQRL

Residue

Distance (Å)

PHE47

3.813

ARG57

4.297

THR59

3.146

TRP60

3.445

GLU108

4.785

Residue

Distance (Å)

ASP305

4.495

LEU306

3.768

ARG309

2.288

ARG310

3.191

ALA313

3.709

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Laminin subunit beta-2 (LAMB2)	PF00053 ; PF00055	26.415 (56/212)	3.59E-04
Peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1)	PF07653 ; PF14604	24.457 (45/184)	2.00E-03


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Hippo signaling pathway	hsa04390	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Hippo signaling pathway - multiple species	hsa04392	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Tight junction	hsa04530	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy

Degree	13	Degree centrality	1.40E-03	Betweenness centrality	1.01E-03
Closeness centrality	2.26E-01	Radiality	1.40E+01	Clustering coefficient	8.97E-02
Neighborhood connectivity	2.76E+01	Topological coefficient	9.83E-02	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

References

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REF 1

Identification of the cis-acting region in the NF2 gene promoter as a potential target for mutation and methylation-dependent silencing in schwannoma. Genes Cells. 2001 May;6(5):441-54.

REF 2

Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2. Nat Commun. 2018 Apr 6;9(1):1338.

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