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FLASH GENE

Symbol

F8

contributors: mct - updated : 22-02-2017

HGNC name	coagulation factor VIII, procoagulant component (hemophilia A)
HGNC id	3546

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
SPECIAL FEATURE	opposite orientation
text	opposite orientation of F8A and F8B in the intron 22
	one F8A copy in intron 22
	F8B in intron 22 for F8B first exon and spliced to exon 23-26 of F8 gene
	exon 19 belongs to those (8 out of 26) that are poorly defined, as witnessed by its weak 3&
	8242;ss, which points toward the presence of functional regulatory elements promoting proper exon inclusion
STRUCTURE	186.94 kb     26 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence
text structure	X controlling element (XCE) functioning similarly to the mouse Xce

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	cen - DXS477 - DXS296 - IDS - DXS460 - DXS304 - DXS334 - DXS341 - DXS455 - DXS49 - DXS497 - DXS256 - DXS374 - DXS258 - DXS175 - GABRA3 - DXS1104 - DXS33 - DXS134 - DXS52 - DXS15 - BGN - ALD - L1CAM - AVPR2 - RGCP@ - DXS439 - UBL4 ,FLNA-RPL10 - G6PD - IKBKG - IP2 - DXS1073 - MPP1 - DKC1 DKC1 - F8 ,DXS115 - DXS551E - VBP1 - DXYS64X - DXS1108 - DXS154 - qter
Authors	Poustka (91), Freije (92), Smahi (94), De Sario (96), Brinke (97), Heiss (98) and others
Text	see FLNA

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000132 26 - 9048 267 2351 - 2007 16487577 Variant 1 large glycoprotein, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex NM_019863 5 splicing 2617 - 216 - 2007 16487577 variant 2 missing exon 1 to 22 (exons 23 to 26 in reading frame) including the phospholipid binding domain (F5/8 type C domain) putative small protein, which consists primarily of the phospholipid binding domain of factor VIIIc (this domain is essential for coagulant activity)

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine neuroendocrine pituitary     highly   parathyroid       highly Nervous nerve       highly

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic monocyte Homo sapiens Cardiovascular endothelial cell Homo sapiens

cell lineage
cell lines
fluid/secretion	plasma

at STAGE

PROTEIN

PHYSICAL PROPERTIES		basic		Hydrophobic
STRUCTURE

motifs/domains	a factor VIII C1b and C2 domains (cooperation between the C1 and C2 domains is necessary for full activity of the factor Xase complex) (
	role of C1 domain is co-operative with other domains of the intact F8 molecule
	a F8 A2 domain that is a key structural element
	a motif implicated in cell adhesion
	domain F5/8 type C2 responsible for phospholipid binding
	three domain F5/8 type A composed of two plastocyanin-like repeats in each and two domains F5/8 type C, behind the hydrophobic surface lies a ring of positively charged residues

secondary structure

a beta sandwich core from which two beta turns and a loop display a group of solvent exposed hydrophobic residues

conjugated

GlycoP

isoforms

Precursor

undergoing multiple cleavage events, preprocoagulant component

HOMOLOGY

interspecies

ortholog to murine F8

Homologene

FAMILY

multicopper oxidase family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular,cytoplasm,organelle,lumen
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,organelle,Golgi
text	synthetized and secreted by the liver

basic FUNCTION	coagulation for FIXa which converts FX to FXa in presence of Ca2+ and phospholipids
	key component of the fluid phase of the blood coagulation system
	functions as a cofactor for Factor IXa in a membrane-bound enzyme complex
	is a novel heme-binding protein
	light chain of F8, which is not biologically active for clot formation, is sufficient for accelerating proteolytic cleavage of VWF by ADAMTS13 under fluid shear stress and (patho) physiological conditions
	may be involved in regulating VWF homeostasis under physiological conditions
	role for F8 and thrombin/F2R in regulating hematopoiesis and its interplay with the bone structure
	F8 stability and half-life is dependent on non-covalent complex formation with von Willebrand factor (VWF) to avoid proteolysis and clearance
	glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

coagulation/hemostasis

text	intrinsic pathway of blood coagulation

PATHWAY

metabolism

signaling

a component	active cofactor, FVIIIa is a trimer composed of A1, A2 and A3-C1-C2 subunits (its role is to markedly increase the catalytic efficiency of factor IXa)
	circulates as a heterodimer composed of heavy (A1A2B domains) and light (A3C1C2 domains) chains

INTERACTION

DNA

RNA

small molecule	metal binding, other,
	calcium Ca2+
	phospholipids
	activated protein held in a complex with Cu++

protein	variant 1 associating with vWF (von Willebrand factor) in a covalent complex
	interacting with MCFD2 and LMAN1, forming stable complexes in liver cells
	binds to phosphatidylserine (PS)-containing membranes through its tandem, lectin-homology, C1 and C2 domains
	F8 accelerates proteolytic cleavage of VWF by ADAMTS13 under fluid shear stress
	light chain, particularly the a3 region in the light chain of F8, contains the major binding site for VWF
	LMAN1 transports coagulation factors V (F5) and VIII (F8)
	LDLR was shown to mediate clearance of blood coagulation factor VIII (F8) from the circulation
	hydrophobic helical stack between the GLA and EGF1 domains of F9 is predicted to be primary interacting region with the A3-C2 domain interface of F8
	LRP1 mediates clearance of blood coagulation factor VIII (F8)
	F8 interacts likely with LRP1 via an extended surface of multiple lysine residues that starts at the bottom of the C1 domain and winds around the F8 molecule
	VWF modulates the internalization and presentation of F8-derived peptides on major histocompatibility complex class II

cell & other

REGULATION

activated by

by thrombin to form a non-covalently linked A1/A2/A3-C1-C2 heterotrimer

Other	VWF may reduce the immunogenicity of F8 by inhibiting the uptake of F8 by antigen presenting cells, the first step in the development of an immune response against a foreign antigen

ASSOCIATED DISORDERS

corresponding disease(s)

F8D , DUPXQ28D

related resource

The Haemophilia A Mutation, Structure, Test and Resource Site (HAMSTeRS)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   FVIII levels above the 75(th) percentile are associated with a significant odds ratio for the occurrence of venous thromboembolism

Susceptibility

risk factor for venous thromboembolism

Variant & Polymorphism

Candidate gene
Marker
Therapy target	use of VWF in conjunction with F8 in the management of patients with haemophilia A (Lacroix-Desmazes 2008)

ANIMAL & CELL MODELS

	multiple eye defects and developmental alteractions in chimeric and transgenic mice are produced by a motif implicated in cell adhesion
	F VIII deficient mice (Vanden Driessche, 99)
	endothelial cells from multiple, but not all, tissues contribute to the plasma F8 pool in the mouse