7f09

Crystal structure of the HLH-Lz domain of human TFE3

Structural highlights

7f09 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:	EDO, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TFE3_HUMAN Epithelioid hemangioendothelioma;MiT family translocation renal cell carcinoma;Alveolar soft tissue sarcoma. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving TFE3 is found in patients with alveolar soft part sarcoma. Translocation t(X;17)(p11;q25) with ASPSCR1 forms a ASPSCR1-TFE3 fusion protein.^[1] Chromosomal aberrations involving TFE3 are found in patients with papillary renal cell carcinoma. Translocation t(X;1)(p11.2;q21.2) with PRCC; translocation t(X;1)(p11.2;p34) with PSF; inversion inv(X)(p11.2;q12) that fuses NONO to TFE3.^[2] ^[3]

Function

TFE3_HUMAN Transcription factor that acts as a master regulator of lysosomal biogenesis and immune response (PubMed:2338243, PubMed:29146937, PubMed:30733432, PubMed:31672913). Specifically recognizes and binds E-box sequences (5'-CANNTG-3'); efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFEB or MITF (By similarity). Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, TFE3 phosphorylation by MTOR promotes its cytosolic retention and subsequent inactivation (PubMed:31672913). Upon starvation or lysosomal stress, inhibition of MTOR induces TFE3 dephosphorylation, resulting in nuclear localization and transcription factor activity (PubMed:31672913). Maintains the pluripotent state of embryonic stem cells by promoting the expression of genes such as ESRRB; mTOR-dependent TFE3 cytosolic retention and inactivation promotes exit from pluripotency (By similarity). Required to maintain the naive pluripotent state of hematopoietic stem cell; mTOR-dependent cytoplasmic retention of TFE3 promotes the exit of hematopoietic stem cell from pluripotency (PubMed:30733432). TFE3 activity is also involved in the inhibition of neuronal progenitor differentiation (By similarity). Acts as a positive regulator of browning of adipose tissue by promoting expression of target genes; mTOR-dependent phosphorylation promotes cytoplasmic retention of TFE3 and inhibits browning of adipose tissue (By similarity). In association with TFEB, activates the expression of CD40L in T-cells, thereby playing a role in T-cell-dependent antibody responses in activated CD4(+) T-cells and thymus-dependent humoral immunity (By similarity). Specifically recognizes the MUE3 box, a subset of E-boxes, present in the immunoglobulin enhancer (PubMed:2338243). It also binds very well to a USF/MLTF site (PubMed:2338243). May regulate lysosomal positioning in response to nutrient deprivation by promoting the expression of PIP4P1 (PubMed:29146937).[UniProtKB:Q64092]^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

The transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) is a member of the microphthalmia (MiT/TFE) transcription factor family. Dysregulation of TFE3 due to chromosomal abnormalities is associated with a subset of human renal cell carcinoma. Little structural information of this key transcription factor has been reported. In this study, we determined the crystal structure of the helix-loop-helix leucine zipper (HLH-Lz) domain of human TFE3 to a resolution of 2.6 A. The HLH-Lz domain is critical for the dimerization and function of TFE3. Our structure showed that the conserved HLH region formed a four-helix bundle structure with a predominantly hydrophobic core, and the leucine zipper region contributed to the function of TFE3 by promoting dimer interaction and providing partner selectivity. Together, our results elucidated the dimerization mechanism of this important transcription factor, providing the structural basis for the development of inhibiting strategies for treating TFE3 dysregulated diseases.

Structural basis for the dimerization mechanism of human transcription factor E3.,Yang G, Li P, Liu Z, Wu S, Zhuang C, Qiao H, Zheng L, Fang P, Lei C, Wang J Biochem Biophys Res Commun. 2021 Jul 2;569:41-46. doi:, 10.1016/j.bbrc.2021.06.091. PMID:34225079^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Heimann P, El Housni H, Ogur G, Weterman MA, Petty EM, Vassart G. Fusion of a novel gene, RCC17, to the TFE3 gene in t(X;17)(p11.2;q25.3)-bearing papillary renal cell carcinomas. Cancer Res. 2001 May 15;61(10):4130-5. PMID:11358836
↑ Sidhar SK, Clark J, Gill S, Hamoudi R, Crew AJ, Gwilliam R, Ross M, Linehan WM, Birdsall S, Shipley J, Cooper CS. The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Hum Mol Genet. 1996 Sep;5(9):1333-8. PMID:8872474 doi:10.1093/hmg/5.9.1333
↑ Weterman MA, Wilbrink M, Geurts van Kessel A. Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15294-8. PMID:8986805 doi:10.1073/pnas.93.26.15294
↑ Beckmann H, Su LK, Kadesch T. TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev. 1990 Feb;4(2):167-79. PMID:2338243 doi:10.1101/gad.4.2.167
↑ Willett R, Martina JA, Zewe JP, Wills R, Hammond GRV, Puertollano R. TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes. Nat Commun. 2017 Nov 17;8(1):1580. PMID:29146937 doi:10.1038/s41467-017-01871-z
↑ Mathieu J, Detraux D, Kuppers D, Wang Y, Cavanaugh C, Sidhu S, Levy S, Robitaille AM, Ferreccio A, Bottorff T, McAlister A, Somasundaram L, Artoni F, Battle S, Hawkins RD, Moon RT, Ware CB, Paddison PJ, Ruohola-Baker H. Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency. Nat Commun. 2019 Feb 7;10(1):632. PMID:30733432 doi:10.1038/s41467-018-08020-0
↑ Lawrence RE, Fromm SA, Fu Y, Yokom AL, Kim DJ, Thelen AM, Young LN, Lim CY, Samelson AJ, Hurley JH, Zoncu R. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science. 2019 Oct 31. pii: science.aax0364. doi: 10.1126/science.aax0364. PMID:31672913 doi:https://dx.doi.org/10.1126/science.aax0364
↑ Yang G, Li P, Liu Z, Wu S, Zhuang C, Qiao H, Zheng L, Fang P, Lei C, Wang J. Structural basis for the dimerization mechanism of human transcription factor E3. Biochem Biophys Res Commun. 2021 Sep 10;569:41-46. PMID:34225079 doi:10.1016/j.bbrc.2021.06.091

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OCA

[1] Heimann P, El Housni H, Ogur G, Weterman MA, Petty EM, Vassart G. Fusion of a novel gene, RCC17, to the TFE3 gene in t(X;17)(p11.2;q25.3)-bearing papillary renal cell carcinomas. Cancer Res. 2001 May 15;61(10):4130-5. PMID:11358836

[2] Sidhar SK, Clark J, Gill S, Hamoudi R, Crew AJ, Gwilliam R, Ross M, Linehan WM, Birdsall S, Shipley J, Cooper CS. The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Hum Mol Genet. 1996 Sep;5(9):1333-8. PMID:8872474 doi:10.1093/hmg/5.9.1333

[3] Weterman MA, Wilbrink M, Geurts van Kessel A. Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15294-8. PMID:8986805 doi:10.1073/pnas.93.26.15294

[4] Beckmann H, Su LK, Kadesch T. TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev. 1990 Feb;4(2):167-79. PMID:2338243 doi:10.1101/gad.4.2.167

[5] Willett R, Martina JA, Zewe JP, Wills R, Hammond GRV, Puertollano R. TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes. Nat Commun. 2017 Nov 17;8(1):1580. PMID:29146937 doi:10.1038/s41467-017-01871-z

[6] Mathieu J, Detraux D, Kuppers D, Wang Y, Cavanaugh C, Sidhu S, Levy S, Robitaille AM, Ferreccio A, Bottorff T, McAlister A, Somasundaram L, Artoni F, Battle S, Hawkins RD, Moon RT, Ware CB, Paddison PJ, Ruohola-Baker H. Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency. Nat Commun. 2019 Feb 7;10(1):632. PMID:30733432 doi:10.1038/s41467-018-08020-0

[7] Lawrence RE, Fromm SA, Fu Y, Yokom AL, Kim DJ, Thelen AM, Young LN, Lim CY, Samelson AJ, Hurley JH, Zoncu R. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science. 2019 Oct 31. pii: science.aax0364. doi: 10.1126/science.aax0364. PMID:31672913 doi:https://dx.doi.org/10.1126/science.aax0364

[8] Yang G, Li P, Liu Z, Wu S, Zhuang C, Qiao H, Zheng L, Fang P, Lei C, Wang J. Structural basis for the dimerization mechanism of human transcription factor E3. Biochem Biophys Res Commun. 2021 Sep 10;569:41-46. PMID:34225079 doi:10.1016/j.bbrc.2021.06.091

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7f09

Crystal structure of the HLH-Lz domain of human TFE3

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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