PAFAH1B1 explained

Platelet-activating factor acetylhydrolase IB subunit alpha or Lisencephaly protein-1 (LIS-1) is an enzyme that in humans is encoded by the PAFAH1B1 gene.^{[1] [2] [3]} The protein plays an important role in regulating the motor protein dynein.^[4]

Function

PAFAH1B1 was identified as encoding a gene that when mutated or lost caused the lissencephaly associated with Miller–Dieker syndrome. PAFAH1B1 encodes the non-catalytic alpha subunit of the intracellular Ib isoform of platelet-activating factor acetylhydrolase, a heterotrimeric enzyme that specifically catalyzes the removal of the acetyl group at the SN-2 position of platelet-activating factor (identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine). Two other isoforms of intracellular platelet-activating factor acetylhydrolase exist: one composed of multiple subunits, the other, a single subunit. In addition, a single-subunit isoform of this enzyme is found in serum.^[3]

According to one study, PAFAH1B1 interacts with VLDL receptor activated by reelin.^[5]

Genomics

The gene is located at chromosome 17p13.3 on the Watson (plus) strand. The gene is 91,953 bases in length and encodes a protein of 410 amino acids (predicted molecular weight 46.638 kilodaltons).

Interactions

PAFAH1B1 has been shown to interact with DYNC1H1,^[6] CLIP1,^[7] NDEL1,^{[8] [9]} NDE1,^[10] PAFAH1B3,^[11] PAFAH1B2,^[11] NUDC,^[12] TUBA1A^[13] and Doublecortin.^[14]

See also

• platelet-activating factor
• PAFAH1B2
• PAFAH1B3

Further reading

• Book: Tjoelker LW, Eberhardt C, Wilder C, Dietsch G, Trong HL, Cousens LS, Zimmerman GA, McIntyre TM, Stafforini DM, Prescott SM, Gray PW . Functional and Structural Features of Plasma Platelet-Activating Factor Acetylhydrolase . Advances in Experimental Medicine and Biology . 1996 . Platelet-Activating Factor and Related Lipid Mediators 2 . 416 . 107–11 . 9131135 . 10.1007/978-1-4899-0179-8_19. 978-1-4899-0181-1 .
• Stafforini DM, McIntyre TM, Zimmerman GA, Prescott SM . Platelet-activating factor acetylhydrolases . The Journal of Biological Chemistry . 272 . 29 . 17895–8 . Jul 1997 . 9218411 . 10.1074/jbc.272.29.17895 . free .
• Yamada Y, Yokota M . Roles of plasma platelet-activating factor acetylhydrolase in allergic, inflammatory, and atherosclerotic diseases . Japanese Circulation Journal . 62 . 5 . 328–35 . May 1998 . 9626899 . 10.1253/jcj.62.328 . free .
• Reiner O, Cahana A, Escamez T, Martinez S . LIS1-no more no less . Molecular Psychiatry . 7 . 1 . 12–6 . 2002 . 11803439 . 10.1038/sj/mp/4000975 .
• Guerrini R, Carrozzo R . Epileptogenic brain malformations: clinical presentation, malformative patterns and indications for genetic testing . Seizure . 11 Suppl A . 7. 532–43; quiz 544–7 . Apr 2002 . 12185771 . 10.1053/seiz.2001.0650. 18943418 . free .
• Wynshaw-Boris A . Lissencephaly and LIS1: insights into the molecular mechanisms of neuronal migration and development . Clinical Genetics . 72 . 4 . 296–304 . Oct 2007 . 17850624 . 10.1111/j.1399-0004.2007.00888.x . 25446883 .
• Mizuguchi M, Takashima S, Kakita A, Yamada M, Ikeda K . Lissencephaly gene product. Localization in the central nervous system and loss of immunoreactivity in Miller-Dieker syndrome . The American Journal of Pathology . 147 . 4 . 1142–51 . Oct 1995 . 7573359 . 1870994 .
• Hattori M, Adachi H, Tsujimoto M, Arai H, Inoue K . Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor acetylhydrolase [corrected] . Nature . 370 . 6486 . 216–8 . Jul 1994 . 8028668 . 10.1038/370216a0 . 4261133 .
• Reiner O, Bar-Am I, Sapir T, Shmueli O, Carrozzo R, Lindsay EA, Baldini A, Ledbetter DH, Cahana A . LIS2, gene and pseudogene, homologous to LIS1 (lissencephaly 1), located on the short and long arms of chromosome 2 . Genomics . 30 . 2 . 251–6 . Nov 1995 . 8586424 . 10.1006/geno.1995.9880 .
• Isumi H, Takashima S, Kakita A, Yamada M, Ikeda K, Mizuguchi M . Expression of the LIS-1 gene product in brain anomalies with a migration disorder . Pediatric Neurology . 16 . 1 . 42–4 . Jan 1997 . 9044400 . 10.1016/S0887-8994(96)00260-3 .
• Sapir T, Elbaum M, Reiner O . Reduction of microtubule catastrophe events by LIS1, platelet-activating factor acetylhydrolase subunit . The EMBO Journal . 16 . 23 . 6977–84 . Dec 1997 . 9384577 . 1170301 . 10.1093/emboj/16.23.6977 .
• Morris SM, Albrecht U, Reiner O, Eichele G, Yu-Lee LY . The lissencephaly gene product Lis1, a protein involved in neuronal migration, interacts with a nuclear movement protein, NudC . Current Biology . 8 . 10 . 603–6 . May 1998 . 9601647 . 10.1016/S0960-9822(98)70232-5 . free . 1998CBio....8..603M .
• Pilz DT, Kuc J, Matsumoto N, Bodurtha J, Bernadi B, Tassinari CA, Dobyns WB, Ledbetter DH . Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1 . Human Molecular Genetics . 8 . 9 . 1757–60 . Sep 1999 . 10441340 . 10.1093/hmg/8.9.1757 . free .
• Sapir T, Cahana A, Seger R, Nekhai S, Reiner O . LIS1 is a microtubule-associated phosphoprotein . European Journal of Biochemistry . 265 . 1 . 181–8 . Oct 1999 . 10491172 . 10.1046/j.1432-1327.1999.00711.x . free .
• Sweeney KJ, Clark GD, Prokscha A, Dobyns WB, Eichele G . Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development . Mechanisms of Development . 92 . 2 . 263–71 . Apr 2000 . 10727864 . 10.1016/S0925-4773(00)00242-2 . 2447495 .

External links

• GeneReview/NIH/UW entry on LIS1-Associated Lissencephaly/Subcortical Band Heterotopia

Notes and References

1. Reiner O, Carrozzo R, Shen Y, Wehnert M, Faustinella F, Dobyns WB, Caskey CT, Ledbetter DH . Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats . Nature . 364 . 6439 . 717–21 . Aug 1993 . 8355785 . 10.1038/364717a0 . 1993Natur.364..717R . 4247668 .
2. Lo Nigro C, Chong CS, Smith AC, Dobyns WB, Carrozzo R, Ledbetter DH . Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome . Human Molecular Genetics . 6 . 2 . 157–64 . Feb 1997 . 9063735 . 10.1093/hmg/6.2.157 . free .
3. Web site: Entrez Gene: PAFAH1B1 platelet-activating factor acetylhydrolase, isoform Ib, alpha subunit 45kDa.
4. Kardon JR, Vale RD . Regulators of the cytoplasmic dynein motor . Nature Reviews Molecular Cell Biology . 10 . 12 . 854–65 . Dec 2009 . 19935668 . 10.1038/nrm2804 . 3394690.
5. Zhang G, Assadi AH, McNeil RS, Beffert U, Wynshaw-Boris A, Herz J, Clark GD, D'Arcangelo G . The Pafah1b complex interacts with the reelin receptor VLDLR . PLOS ONE . 2 . 2 . e252 . 2007 . 17330141 . 1800349 . 10.1371/journal.pone.0000252 . 2007PLoSO...2..252Z . Mueller . Ulrich . free .
6. Tai CY, Dujardin DL, Faulkner NE, Vallee RB . Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function . The Journal of Cell Biology . 156 . 6 . 959–68 . Mar 2002 . 11889140 . 2173479 . 10.1083/jcb.200109046 .
7. Casper Hoogenraad. Coquelle FM, Caspi M, Cordelières FP, Dompierre JP, Dujardin DL, Koifman C, Martin P, Hoogenraad CC, Akhmanova A, Galjart N, De Mey JR, Reiner O . LIS1, CLIP-170's key to the dynein/dynactin pathway . Molecular and Cellular Biology . 22 . 9 . 3089–102 . May 2002 . 11940666 . 133759 . 10.1128/MCB.22.9.3089-3102.2002 .
8. Toyo-oka K, Shionoya A, Gambello MJ, Cardoso C, Leventer R, Ward HL, Ayala R, Tsai LH, Dobyns W, Ledbetter D, Hirotsune S, Wynshaw-Boris A . 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome . Nature Genetics . 34 . 3 . 274–85 . Jul 2003 . 12796778 . 10.1038/ng1169 . 10301633 .
9. Niethammer M, Smith DS, Ayala R, Peng J, Ko J, Lee MS, Morabito M, Tsai LH . NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein . Neuron . 28 . 3 . 697–711 . Dec 2000 . 11163260 . 10.1016/S0896-6273(00)00147-1 . 11154069 . free .
10. Efimov VP, Morris NR . The LIS1-related NUDF protein of Aspergillus nidulans interacts with the coiled-coil domain of the NUDE/RO11 protein . The Journal of Cell Biology . 150 . 3 . 681–8 . Aug 2000 . 10931877 . 2175200 . 10.1083/jcb.150.3.681 .
11. Sweeney KJ, Clark GD, Prokscha A, Dobyns WB, Eichele G . Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development . Mechanisms of Development . 92 . 2 . 263–71 . Apr 2000 . 10727864 . 10.1016/S0925-4773(00)00242-2 . 2447495 .
12. Morris SM, Albrecht U, Reiner O, Eichele G, Yu-Lee LY . The lissencephaly gene product Lis1, a protein involved in neuronal migration, interacts with a nuclear movement protein, NudC . Current Biology . 8 . 10 . 603–6 . May 1998 . 9601647 . 10.1016/S0960-9822(98)70232-5 . free . 1998CBio....8..603M .
13. Sapir T, Elbaum M, Reiner O . Reduction of microtubule catastrophe events by LIS1, platelet-activating factor acetylhydrolase subunit . The EMBO Journal . 16 . 23 . 6977–84 . Dec 1997 . 9384577 . 1170301 . 10.1093/emboj/16.23.6977 .
14. Caspi M, Atlas R, Kantor A, Sapir T, Reiner O . Interaction between LIS1 and doublecortin, two lissencephaly gene products . Human Molecular Genetics . 9 . 15 . 2205–13 . Sep 2000 . 11001923 . 10.1093/oxfordjournals.hmg.a018911 . free .