PAFAH1B1 - dismech genes

Normal function · from ai-gene-review (P43034, commit 79fe13b38970) · AI-generated, not KB evidence

PAFAH1B1 encodes LIS1, a conserved WD40 beta-propeller protein with an N-terminal LisH dimerization domain. Its principal function is regulation of cytoplasmic dynein-1: LIS1 dimers bind the dynein motor domain and dynactin p150, promote assembly of active dynein-dynactin-adaptor complexes and dynein targeting to microtubule plus ends, cargos, kinetochores, the cell cortex and the nuclear envelope, and sustain dynein force production under load. Acting with NDEL1/NDE1 at the centrosome, LIS1 couples the nucleus to the centrosome during neuronal migration (nucleokinesis), drives interkinetic nuclear migration and division of neural progenitors, and supports mitotic spindle orientation, chromosome attachment and retrograde axonal transport. Heterozygous loss of PAFAH1B1 causes classical lissencephaly and subcortical band heterotopia, and deletion with neighbouring genes causes Miller-Dieker syndrome. Independently, LIS1 is the non-catalytic regulatory beta subunit of cytosolic platelet-activating factor acetylhydrolase Ib, binding the PAFAH1B2/PAFAH1B3 catalytic dimer that hydrolyses the sn-2 acetyl group of PAF.

LIS1 dimers bind the cytoplasmic dynein-1 motor domain and dynactin p150 to regulate dynein: they promote assembly of active dynein-dynactin-adaptor complexes, target dynein to microtubule plus ends and cargos, and induce a persistent high-load force state. With NDEL1/NDE1 this drives dynein-dependent nuclear translocation toward the centrosome in migrating neurons and progenitors, mitotic spindle orientation and retrograde axonal transport.

molecular function: cytoskeletal motor regulator activity · directly involved in: nuclear migration along microtubule; neuron migration; interkinetic nuclear migration; establishment of centrosome localization; establishment of mitotic spindle orientation; retrograde axonal transport · locations: centrosome; astral microtubule; kinetochore; cell cortex; nuclear envelope; perinuclear region of cytoplasm · in complex: microtubule associated complex

The LIS1 WD40 propeller binds the dynein heavy chain motor domain and intermediate chain and dynactin, the physical basis of dynein regulation; LIS1 is recruited to kinetochores via dynein/dynactin.

molecular function: dynein complex binding · directly involved in: nuclear migration along microtubule · locations: kinetochore; centrosome

As the non-catalytic beta subunit of cytosolic PAF acetylhydrolase Ib, a LIS1 homodimer binds the PAFAH1B2/PAFAH1B3 catalytic dimer and modulates its activity; catalysis of PAF deacetylation resides in the alpha subunits. This role is distinct from, and competes structurally with, LIS1 binding to NDEL1/dynein.

molecular function: enzyme regulator activity · locations: cytosol · in complex: 1-alkyl-2-acetylglycerophosphocholine esterase complex

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Lissencephaly Spectrum Disorders	untyped Loss of function	mechanism: LIS1 Progenitor Spindle Orientation Defect; LIS1-NUDEL-Dynein Nucleokinesis Failure subtype: Classic/LIS1 scoped to subtype: Classic/LIS1
Miller-Dieker Lissencephaly Syndrome	untyped Causal contiguous-gene deletion	mechanism: 17p13.3 Contiguous-Gene Deletion

Mechanism modules · computed from kb/

microtubule_dependent_neuronal_migration_failure via Lissencephaly Spectrum Disorders named in the module itself
neural_progenitor_centrosome_spindle_dysfunction via Lissencephaly Spectrum Disorders named in the module itself