Human membrane recycling proteins

Details Human membrane recycling proteins Human membrane recycling proteins

1999-07-23

2001-05-22

Carlson, Karen Cochrane (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S300000, C530S350000

Reexamination Certificate

active

06235715

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of human membrane recycling proteins, and to the use of these sequences in the diagnosis, treatment, and prevention of neurological, endocrine, immunological and cell proliferative disorders.
BACKGROUND OF THE INVENTION
Intercellular communication is essential for the development and survival of multicellular organisms. Cells communicate with one another through the secretion and uptake of protein signaling molecules. The uptake of proteins into the cell is achieved by endocytosis, in which the interaction of signaling molecules with the plasma membrane surface, often via binding to specific receptors, results in the formation of plasma membrane-derived vesicles that enclose and transport the molecules into the cytosol. The secretion of proteins from the cell is achieved by exocytosis, in which molecules inside of the cell are packaged into membrane-bound transport vesicles derived from the trans Golgi network (TGN). These vesicles fuse with the plasma membrane and expel their contents into the surrounding extracellular space. Endocytosis and exocytosis result in the removal and addition of plasma membrane components, and the recycling of these components is essential to maintain the integrity, identity, and functionality of both the plasma membrane and internal membrane-bound compartments.
The endocytic and exocytic pathways converge in internal membrane-bound compartments called endosomes that function in shuttling molecules to and from the TGN and the plasma membrane. In the endocytic pathway, vesicles from the plasma membrane fuse with the endosomal compartment where the internalized signaling molecules dissociate from their receptors. The free receptors are then recycled back to the plasma membrane in vesicles derived from the endosomal compartment. Likewise, in the exocytic pathway, transport vesicles derived from the TGN fuse with the plasma membrane, expel their molecular cargo, and reform. The emptied transport vesicles then recycle back to the TGN via the endosomal compartment.
Certain differentiated cell types have highly specialized and regulated endocytic or exocytic pathways. For example, pancreatic cells package and store digestive enzymes in TGN-derived vesicles called secretion granules until the cells are stimulated by hormonal signals to secrete these enzymes. Similarly, mast cells of the immune system package and store secretion granules containing histamine molecules until stimulated by allergic signals. Neuronal cells package and store neurotransmitters in synaptic vesicles. In response to an action potential, the synaptic vesicles rapidly release their neurotransmitters into the synaptic cleft by fusing with the plasma membrane. The neurotransmitters are taken back up into the neuronal cell by endocytosis, and the neurotransmitters are recycled into synaptic vesicles via the endosomal compartment. (Sudhof, T. C. and Jahn, R. (1991) Neuron 6:665-677; and Sudhof, T. C. et al. (1993) Cell 75:1-4.)
Biochemical and immunocytological studies in rat have shown that TGN- and endosome-derived vesicles contain characteristic integral membrane proteins called SCAMPS, secretory carrier membrane proteins. (Brand, S. H. et al. (1991) J. Biol. Chem. 266:18949-18957.) SCAMP 37, in particular, contains structural motifs that include a potential N-terminal metal ion-binding domain; a leucine zipper domain; two zinc finger nucleotide-binding domains; and four putative membrane-spanning helices. SCAMPs are associated with synaptic vesicles in neuronal cells; secretion granules in endocrine cells; and plasma membrane-derived endocytic vesicles in non-specialized fibroblast cells. (Brand, S. H. and Castle, J. D. (1993) EMBO 12:3753-3761; Laurie, S. M. et al. (1993) J. Biol. Chem. 268:19110-19117.) Because of their ubiquitous presence in vesicles from diverse cellular sources, it is proposed that SCAMPs may play a role in a general cell surface recycling mechanism by regulating vesicular traffic to and from the TGN and plasma membrane. This role would be central to intercellular communication mediated by neurotransmitters, hormones, growth factors, and other signaling molecules involved in cell proliferation and the immune response, and in neurological or endocrine function.
The discovery of new human membrane recycling proteins and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of neurological, endocrine, immunological and cell proliferative disorders.
SUMMARY OF THE INVENTION
The invention features substantially purified polypeptides, human membrane recycling proteins, referred to collectively as “HMRP” and individually as “HMRP-1” and “HMRP-2.” In one aspect, the invention provides a substantially purified polypeptide, HMRP, comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, a fragment of SEQ ID NO:1, and a fragment of SEQ ID NO:3.
The invention further provides a substantially purified variant of HMRP having at least 90% sequence identity to the amino acid sequences of SEQ ID NO:1 or SEQ ID NO:3, or to a fragment of either of these sequences. The invention also provides an isolated and purified polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, a fragment of SEQ ID NO:1, and a fragment of SEQ ID NO:3. The invention also includes an isolated and purified polynucleotide variant having at least 90% sequence identity to the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, a fragment of SEQ ID NO:1, and a fragment of SEQ ID NO:3.
Additionally, the invention provides a composition comprising a polynucleotide encoding the polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, a fragment of SEQ ID NO:1, and a fragment of SEQ ID NO:3. The invention further provides an isolated and purified polynucleotide which hybridizes under stringent conditions to the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, a fragment of SEQ ID NO:1, and a fragment of SEQ ID NO:3, as well as an isolated and purified polynucleotide which is complementary to the polynucleotide encoding the polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, a fragment of SEQ ID NO:1, and a fragment of SEQ ID NO:3.
The invention also provides an isolated and purified polynucleotide comprising a polynucleotide having a sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, a fragment of SEQ ID NO:2, and a fragment of SEQ ID NO:4. The invention further provides an isolated and purified polynucleotide variant having at least 90% sequence identity to the polynucleotide comprising a polynucleotide having a sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, a fragment of SEQ ID NO:2, and a fragment of SEQ ID NO:4, as well as an isolated and purified polynucleotide which is complementary to the polynucleotide comprising a polynucleotide having a sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, a fragment of SEQ ID NO:2, and a fragment of SEQ ID NO:4. The invention also provides a polynucleotide fragment useful for designing oligonucleotides or to be used as a hybridization probe which comprises a polynucleotide having a sequence selected from the group consisting of nucleotides 438-462 of SEQ ID NO:2 and nucleotides 304-330 of SEQ ID NO:4.
The invention further provides an expression vector containing at least a fragment of the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, a fragment of SEQ ID NO:1, and a fragment of SEQ ID NO:3. In another aspect, the expression vect

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